The pathophysiology of murine retrovirus-induced leukemias

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THE PATHOPHYSIOLOGY OF MURINE RETROVIRUS-INDUCED LEUKEMIAS Authors:

Ron D. Schiff Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York Allen Oliff Cancer Research Merck Sharp and Dohme Research Laboratories Westpoint, Pennsylvania

Referee:

Alan Berns~eia

Department ol Biophysicsi and Molecular and Developmental Biolog? Mr. Sinai Hospital Research Institute Toronto, Canada

I. I N T R O D U C T I O N Murine type C retroviruses, or RNA tumor viruses, cause a variety of neoplastic and degenerative diseases in mice. The pathophysiology of these disorders is complex and incompletely understood. However, the advent of recombinant DNA techniques has provided new insights into the interactions between viral and host-cellular genetic information which underlie these diseases. The murine type C retroviruses may be grouped into two broad classes based on (1) their replication-competence and (2) the mechanisms by which they cause disease in susceptible animals or transform cells in culture. The routine sarcoma viruses (MSVs) are replication-defective, acutely transforming retroviruses~ which cause sarcomas and erythroleukemia, generally with short latency. These viruses arise by recombination between the genomes of replication-competent murine leukemia viruses (MuLVs) and the cellular DNA of their marine hosts. 21'~6't87'~e2"s~~ This recombination event results in the loss from the viral genbmc of sequences which are required for virus replication. Consequently, coinfection by replication-competent helper viruses is necessary to propagate an MSV infection. 2" The deleted viral sequences are replaced by cellular sequences which are responsible for the ability of MSVs to transform fibreblasts in culture or to induce mesenchymal tumors or erythrolenken~ia in vi,zo. These transduced cellular genetic elements are called oncogenes. Many studies of viral onco:v genes and the expression of their cellular counterparts in normal and neoplastic tissu~ have enhanced our understanding of viral carcinogenesis. The MSVs and their mechanisms of cell transformation will not be discussed in detail in this article; these subjects are included in several excellent reviews published elsewhere. 44'96'~z'~4~ In contrast to the acutely transforming MSVs, the MuLes do not contain transduced cellular genes. MuLVs are replication-competent retroviruses which are unable to transform cultured fibroblasts but can cause hematopoietic malignancies (leukemias, lymphomas, and plasma cell dyscrasias) and certain degenerative diseases in mice. Since no oncogene is present, other regions of the viral genome must subserve the transforming function. The pathophysiology of MuLV-induced disease is less clearly understood than the various mechanisms of oncogene-mediated neoplasia. However,

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CRC Critical Reviews in Ontology~Hematology

~

viri0n

~\~ attachment

budding ~

virion ~

5'"~',k reverse Itanscribe .... ~ nl~A

preCursor~ inlernalfl~P15"~~

/

vtrionJ ~t~lp12. reverse\i/

/x /

. r e t e i n s ~ P 30 irans~- \ ~ ] v [ I~lplO criptase \~ [

J.

"~, .....

-'~ Cytoplasm I

@ONA --\ "" t-" ~ tntegr.ateo LJ.nGAG60t ENVLT, proviral

__ precursor\--.... . . . . .

.=

\

mm_.._A

_

FIGURE I. Schematic diagram of MuLV replication. Virion attachment occurs at the cell surface via specific cell surface receptors. Viral uncoatin$ and reverse transcription occur in the cytoplasm. Viral DNA integrates into the cell genome and directs the synthesis of new viral RNAs in the cell nucleus. These newly made RNAs thca migrate to the cytoplasm where they direct the synthesis of viral proteins, The vires completes its life cycle as viral RNA is incorporated into new viral particles which bud off from the external membrane of the infected cell, recent discoveries have identified specific regions of the MuLV $enome which harbor determinants of leukemogenicity. We and other investigators have characterized these regions and begun to define their functions in leukemogenesis. Our discussion of MuLV-induced leukemogenesis will focus on these findings and their pathophysiologic implications. To place these studies in perspective, we will first present a brief review of MuLV replication and genetics. II. R E P L I C A T I V E C Y C L E O F T H E M U R I N E L E U K E M I A V I R U S E S The replicative cycle of the retroviruses (Figure 1) is characterized by a requirement for the synthesis ~f a DNA intermediate, the provirus, which becomes covalently integrated into the DNA of the host cell. 'sz This requirement distinguishes the retroviruses from all other viruses which employ RNA as their genetic material, The sequence of events involved in MuLV replication is typical of the broader class .qf replication-competent retroviruses. This group also includes the nondefective avian sarcoma viruses (ASVs), which historically have provided most of our fundamental insights into the retrovira! replicative cycte and genetics.

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A. Synthesis of Proviral DNA The provirus is a'double-stranded DNA copy of the single-stranded RNA genome. Its synthesis is the first critical molecular event in the viral replicativo cycle, occurring shortly after a virus particle penetrates the plasma membrane of a susceptible cell. Proviral DNA synthesis is catalyzed by reverse transcriptase, a unique viral enzyme which possesses RNA-directcd "'~6~ and DNA-directcd ~4''9''j9~'3~'~'~'~ DNA polymerase activities, and is also able to degrade the RNA strand of RNA. DNA hybrids (ribonuclease H aaivity), z''4~s These enzymatic activities are required for ;he synthesis of the first and second strands of viral DNA. initially, viral genomic RNA is used as the template to form a.~ RNA. DNA hybrid. The RNA strand of the hybrid is subsequently degraded, and the second DNA strand is simultaneously synthesized using the first strand as a template. A molecule of cellular transfer RNA is hydrogen-bonded to the 5' terminus of ~.hr RNA genome and serves as a primer for the initiation of RNAdirected DNA synthesis. '~176176176 In the case of the MuLVs, the primer is proline tRNA (tRNA~*~ "~'4"'~' A fourth enzymatic activity, DNA endonuciease, is also associated with the reverse transcriptase molecule. ~ ' ~ , z ~ 4 . ~ ' , ~ . * ~ . ~ . ~ However, the precise role of the DNA endonuclease activity in retrovirus replication remains a matter of speculation. The purification, tool wt (70,000 to 85,000 daltons), polypeptide structure, and in vitro enzymatic properties of the MuLV reverse transeriptase molecule have been characterized. ~~ 4 tO. 413.43J~.439,$45.6 70,705

The final product of reverse transcripti6n is a linear duplex DNA molecule 5 to 10 kbase pairs in length, whose genetic structure corresponds to that of the 35 S RNA of the viral genome. This DNA species possesses extensive terminal nucleotide-sequence redundancy (long terminal repeats, or LTRs), which arises during reverse transcription of the 5' and 3' termini of the viral RNA genome. ~~176176176176 The detailed mechanism by which viral DNA is synthesized remains largely speculative. ~~ B. integration of the Provirus Viral DNA synthesis is a cytoplasmic event. '93.'7'3~176176 The linear duplex DNA produced by reverse transcriptase is transported to the nucleus, where it undergoes circularization and supercoiling. ~93'2~ The formation of superhelical vira! DNA appears to be a prerequisite for the covalent integration of one or more copies of the provirus into cellular DNA. 4~2~176176176176Evidence that circut.arization and supercoiling of viral DNA are required for integration is derived from experiments in which ethidium bromide treatment of uninfected duck cells was used to inhibit circularization and supercoiling of newly synthesized linear duplex DNA after infection with ASV. No integrated viral sequences could be detected in these coils after infection. "~'~97 In the absence of ethidium bromide, integration occurs between 6 and 24 hr after infection.,4 370 ,703 The structure of proviral DNA and its cellular integration sites have been intensively investigated. Proof that at least one copy of the viral gcnome is integrated comes from transfection experiments which showed that high-tool wt DNA isolated from ASV- or MSV-transformed cells 4:an be taken up by cultured chick embryo fibroblasts; fibrob[asts incorporating this DNA become transformed. 9B"t ~ *~16t-2~,.~os.,~.6~o Restriction m~pping of cellular DNA adjacent to integrated proviral DNA has revealed that integration is not confined to a unique site, but may occur at many sites in the host geno m e . 16,LT.31.:)2,e~z.9'l.a2z,z~'s,276.2Bs.31s.sz4.ss$.~2.~JO,690 Molecular hybridization analysis has demonstrated that up to 20 copies of proviral DNA are integrated into the genome of cells chronically infected with retroviruses) '6.~~176176 Infectious proviral DNA, however, is integrated in only one or a few sites. Higher copy numbers may be achieved in acute

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infections, but cell death results if the additional copies of the provirus are not somehow inactivated or eliminated from the cellular genome. 3''32 Restriction mapping has also been appl.ied to studies of the internal structures of the integrated provirus and its unintegrated precursors. The integrated proviral sequences are colinear with unintegrated, linear duplex viral DNA, 9''275'J'''su''a Cloned circular viral DNA generally contains one or two copies of the LTR per molecule. In molecules containing two copies, these sequences are found as a direct tandem repeat. '~'~2z,24~,~72,3~7.sas'6~ The LTR itself contains inversely arranged repetitive sequences (inverted repeats) i to 2 dozen base pairs in length near its termini. ~z~-~-~z*~~ This structural feature, which is shared by certain transposable elements in bacterial DNA, may be required for the circularization or integration of viral DNA, Two 5'-terminal adenosine residues and two 3'-terminal thymidine residues are found in linear duplex viral DNA but are absent from the integrated provirus. ~2~'j*~.6~176176 These nucleotides may define a site where staggered cuts are made in circular viral DNA during integration. A direct repeat of four to six base pairs of cellular DNA is found on either side of each copy of integrated proviral DNA. These cellular sequences are present in a single copy prior to integration, suggesting that duplication occurs during the process of integration. x3 , . 2 6 ~ . z ~ 4 . 3 , ~ . 6 0 a .602.605.6~8 The precise mechanism of recombination between viral and cellular DNA during integration of the provirus remains uncertain. Several models for imegration have been proposed, ~~ but none is convincingly supported by experimental evidence. The findings that the reverse transcriptase-associated DNA endonuclease activity of the avian retroviruses can bind to and nick cloned superhelical viral DNA at specific sites within the LTR '4~.~'*,'0~ suggests that this enzyme activity may function to prepare the provirus for integration. Further support for this hypothesis is derived from recent demonstrations that site-directed deletion or missense mutations in the predicted endonuclease coding domain of cloned viral DNA result in defective proviral integration.'~~ Once completed, integration of the provirus sets the stage for: (1) replication of virus-specific DNA with consequent vertical transmission of the provirus; (2) transcription of virus-specific RNA and subsequent steps in the expression of integrated viral genes; (3) introduction of frame-shift mutations into cellular DNA caused by the insertion of viral sequences into the host genome; TM and (4) cell transformat;'m under the control of viral oncogenes or other genetic elements. C. Expression of Integrated Proviral Genes Integrated proviral DNA undergoes replication and transcription as part of the cellular genome, under the control of host enzymes. Remarkably little has been written about the replication of the integrated provirus, but the virus-specific sequences appear to be duplicated once per cell cycle, like cellular DNA. The dependence of proviral replication on cellular DNA synthesis is suggested by the finding that the production of infectious retroviruses by cells harboring integrated proviruses is decreased by treating these cells with inhibitors of DNA synthesis. 's~.47~.~'' DNA-directed synthesis of viral RNA has been documented by the finding that acfinomycin D inhibits virus production by infected ceils, la.~s.2~.66~'7~~ Fan and Baltimore, ''~ Leong et al., ~ and Monroy et al. 4z9 developed radioactively labeled virusspecific DNA probes for the quantitation of virus-specific RNA by nucleic acid hybridization. DNA complementary to virus-specific RNA (eDNA) was synthesized in vitro (in the presence of radioactively labeled deoxyribonucleotides) from the virion RNA of avian myeloblastosis virus (AMV) by the endogenous RNA-directed DNA polymerase activity present in the virus. These probes were used to detect AMV- or ASVspecific RNA synthesized intracellularly or in isolated nuclei or nuclear chromatin frac-

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tions from infected cells. The investigators found that virus-specific transcription is dependent upon the presence of proviral DNA. Furthermore, the quantity of RNA synthesized in retrovirus-infected cells is greater than that expected from random transcription of the entire cellular genome, suggesting that transcription is a selective process favoring expression of virus-specific D N A sequences. Similar results were obtained by Weissmann et al. 93.7,~ using unlabeled eDNA probes to detect radioactively labeled virus-specific RNA. Transcription of the integrated provirus begins 6 to 7 hr after infection, 2~'~6t Since virus-specific RNA synthesis is inhibited by aipha-amanitin, an inhibitor of the cellular enzyme RNA polymerase II, it appears that RNA polymerase ii directs the transcription of proviral DNA. ~ja.2s3"Ssr'7~6A single initiation site for transcription of integrated proviral DNA has been mapped within the LTR on the basis of analyses of the size and composition of nascent virus-specific RNA molecules synthesized in vivo or in vitro."."" The promoter for transcription is also found in the LTR, just :5' to the initiation site 6.4$,65.68,99.104.131.242,467.60t.644.1i~.|.c~$7.67~.$17.74pRecently, transcriptional enhancer sequences in the form of tandem direct repeats have been found in the LTR of Moloney routine sarcoma virus (Mo-MSV). ~a~'5~ The site at which transcription terminates is not yet clearly identified. The characteristics and fate of the viral RNA transcribed from integrated proviral DNA have been studied extensively. Like cellular messages, virus-specific mRNA must be transported from the nucleus to the cytoplasm, where it serve~ as a template for viral protein synthesis. 4"6.*'~Newly synthesized viral RNA must be processed for its messenger function before it is transported to the cytoplasm. This post-transcriptional processing includes the addition of a 5'-terminal methyl "cap," methylation of certain internal adenylate residues, '~ and polyadenylation of the 3' terminus, ~e~Each of these structural features has been identified within the genomic RNA species found in mature retrovirus particles. However, the timing and intraceilular location at which these alterations occur, and the enzymatic mechanisms involved, have not been elucidated. Nucleic acid hybridization analysis using eDNA probes specific for various regions of the retrovirus genome has identified two size classes of virus-specific mRNA in avian or mammalian retrovirus-infected ceils: 35S mRNA, which is similar in length to the genomic RNA of the retroviruses, and 20-30S mRNA. s''sr''~''69tT-;,lOll,:lSS.:~2tl.ql3r~70,,~Pt,Oli-6S:l.TZ4 The 20-30S mRNA species represent a sequence of at least I00 nucleotides from the 5' terminus of the 35S RNA molecule spliced to a larger segment from the 3'-terminal half of 35S RNA. ~~176176 However, the mechanism by which the primary virus-specific transcription products are processed is not known. In vitro translation of avian or mammalian retroviral mRNA in cell-free systems or following microinjection into X e n o p u s ooeytes has demonstrated that the viral internal structural proteins and reverse transcriptase polypeptides are translated from the 5' half of genome-sized mRNA. ~~176176 soo.so,.s~o.~or.~.,~z.~ The glycoproteins of the viral envelope and the products of the oncogenes of the nondefectivr avian retroviruses are translated from the portions of the subgenomic RNA species derived from the 3' half of the genpine. "=s.4~'.4st,so~176176 The association of the various viral RNA species with free and membrane-bound polyribosomes has been investigated using nucleic acid hybridization analysis in conjunction with cell-fractionation techniques. The full-length m'RNA molecules encoding the s virion proteins and reverse transcriptase are localized primarily in free polyribosomes. The subgenomic mRNA species encoding the envelope glycoproteins and oneogene products are found predominantly in membrane-bound polyribosomes, ~*s.~*~'~'~'s*~''~ Post-translational events include a complex sequence of proteolytic cleavages of the polyprotein precursors to the internal structural, reverse transcriptase, and envelope

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polypeptides. Certain poiypeptides undergo glycosylation or phosphorylation. It is worth noting that these post-translational modifications impose an additional level of regulation on the expression of integrated retroviral genes. The RNA transcribed from integrated proviral DNA does not serve exclusively as a template for viral protein synthesis. Some RNA molecules must be packaged into progeny virions in productive infections. Virion RNA and mRNA are structurally identical but may be distinguished on a functional basis. Inhibition of viral RNA synthesis in MuLV-infected cells by actinomyein D does not interrupt the synthesis of viral proteins from preexisting viral mRNA, but cellular rather than viral RNA is incorporated into the virions released from these cells. 35s,~56The assembly of retroviruses occurs in the cytoplasm. Newly synthesized viral genomic RNA is encapsidated into viral internal structural proteins and envelope glycoproteins.~as.74~ The assembled virions mature at the plasma membrane, from which the viral envelope acquires lipids and cellular glycoproteins during the process of budding, :~a~6.~2',7" The release of mature virions from infected cells completes the replicative cycle of the retroviruses. Ill. VIRUS C L A S S I F I C A T I O N Classification of the murine retroviruses on the basis of replication competence and acute transforming ability has been discussed. According to this scheme, MuLVs are replication-competent retroviruses which are unable to transform cultured fibroblasts. Nonetheless, MuLVs can cause hematopoietic malignancies and certain chronic diseases in vivo. The naturally occurring and laboratory-derived MuLV strains may also be categorized according to the nature of the diseases they ~ause in vivo, their celltropism in vitro, and their genetic composition (Table 1). A. Pathologic Classification The first MuLV was isolated from mice which had been inoculated as newborns with a cell-free extract of leukemic cells from AKR mice. ~ze,229Serial passage of the initial isolate through multiple generations of newborn mice led to the establishment of the highly ]eukemogenic Gross passage-A strain. 23~The Gross and Akv strains of MuLV cause thymic (T-cell) leukemias and lymphomas with a minimum latent period of 10 to 12 weeks. The Moloney routine leukemia virus (Mo-MuLV) is also a thymotropic virus capable of inducing T-cell malignancies. Mo-MuLV was isolated from mice which had been inoculated with a cell-free extract.from a transplantable mouse sarcoma. (1~,'~7The neoplasms associated with these viruses may arise from exogenous infection or from the activation of endogenous viruses. Endogenous viruses are produced from viral genetic information integrated in the cellular genome, Once integrated into the DNA of germ ceils, the viral genome is transmitted vertically from generation to generation. Endogenous viruses may be activated spontaneously or by treatment of the host cell or animal with X-irradiation or chemical carcinogens. Expression of endogenous viral genomes can result in the production of infectious virus particles. In the case of the Gross passage-A, Akv, and Moloney strains of MuLV, activation of endogenous viral genomes is associated with the development of thymic leukemias and lymphomas. 9 Friend virus was originally isolated from a Swiss mouse which had developed erythroleukemia after inoculation with Ehrlich ascitcs mouse carcinoma cells,'9~ The erythrolenkemia caused by Friend's initial isolate (FV-A) was manifested by anemia, hepat o s p l e n o m e g a l y , circulating p r o e r y t h r o b l a s t s , and increased numbers of proerythroblasts in the bone marrow. Other isolates of Friend virus (FV-P) produce erythroleukemia characterized by the presence of polyeythemia-~'ather than anemia. '~176176 In a minority of infected mice, Friend virus induces acute myeloid leukemias rather than erythroleukemia. All isolates of Friend virus contain at least two

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Table 1 C L A S S I F I C A T I O N OF T H E M U R I N E L E U K E M I A VIRUSES C O M M O N L Y USED IN L E U K E M I A RESEARCH

Virus Akv MuLV

Replication Cell c o m p e t e n t tropism +

Eco

Gross passage-A

+

Eco

Moloney MuLV

+

Eco

SL3-3 MuLV

-*-

Eco

Fr}end M~LV

+

Eco

Friend SFFV Rauscher SFFV Amphotropic MuLV

---+

NA NA Ampho

MCF MuLVs

+

Poly

Disease Thymic leukemia and ~mphoma Thymic leukemia and lymphoma Thymic leukemia and lymphoma Thymic leukemia and ]ymphoma Erythroleukemia Myeloid leukemia Erythroleukemia Erythroleukemia Thymicleukemia Hind.limb paralysis or ttonpathogertic Thymic leukemia Erythroleukemia

Note: $FFV = spleen focus forming virus, MCF - mink cell focus

forming virus, Eco - ecotropi,m (i.e., viruses that can infect only murine ceils), NA = not applicable, Ampho = amphotropism, Poly = poly-tropism (both amphotropism and poly-trol~ism refer to viruses that can infect either murine or nonmurine ceils). viral components: (1) Friend murine leukemia virus (F-MuLV), a replication-competent " h e l p e r " virus It3"62s which can induce erythroleukemia, 3'7.**~.675 thymir leukemia, tee or myeloid leukemia 7',s'* in neonatal mice; and (2) Friend spleen focus.forming virus (F-SFFV), a replication-defective virus which induces loci of erythroblasts in the spleens of infected animals and is responsible for the ability of the Friend virus c o m p l e x to i n d u c e r a p i d c r y t h r o l e u k e m i a s in a d u l t as well as n e w b o r n J[~ice.

14.~.378.407.62s.627,673.674

The Rauscher leukemia virus was initially isolated from a mouse ascites tumor that arose from in vivo passage of cells from a previously established mouse viral l e u k e m i # 'a and was then itself passaged in ~ivo through adult Swiss mice and weanling B A L B / c mice. s'~ Like Friend virus, Raus=her virus consists of two components, the replication-competent Rauscher murine leukemia virus ~ and the replication-defective Rauscher SFFV. '~,*~s Within 14 days after inoculation with the Rauscher leukemia virus complex, neonatal or adult mice develop crythroleukemia characterized by anemia, hepatosplenomegaly, and the presence o f proerythroblasts in the peripheral blood and in excessive numbers in the bone marrow. The acute manifestations of Rauscher leukemia virus disease are dependent upon the presence of the SFFV component. ~*~ Evolution to acute lymphoblastic leukemia occurs after severa[ weeks in surviving animals. 4~,st~ This event appears to be controlled by the replication-competent helper virus, st' The SL3-3 virus was isolated from a cell line derived from a spontaneous thymic lymphoma in an A KR mouse. 2".s~' This virus causes thymic leukemia or lymphoblastic lymphoma in several strains of mice within 10 to 12 weeks after neonatal inocula-

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The myeloproliferative sarcoma virus (MPSV) is a variant of Mo-MSY. MPSV was isolated from a BALB/c mouse after in vivo passage of cells and ceil-free extracts of a Mo-MSV-indueed sarcoma, e4 Like Friend virus and Rauscher virus, isolates of MPSV contain a replication-defective SFFV'" and cause erythroleukemia or rnyeloid leukemias in infected animals. ~9 However, MFSV also retains the acute transforming capacity of Mo-MSV, and is able to induce sarcomas in vivo and transform fibroblasts in vitro. ~' The Abelson murirte leukemia virus (Ab-MuLV) was isolated from a BALB/r mouse which had undergone chemical thymectomy by repeated administration of prednisolone during the neonatal period, and was then inoculated with Mo-MuLV. 1,~ MoMuLV is invariably present as a r~plication-competent helper virus in Ab-MuLV stocks. Ab-MuLV induces a nonthymic (pre-B-eell) lymphoproliferative disorder within 4 weeks after inoculation of BALB/c t'2`4~'s~ or athymic nude mice. s~ Abelson virus can also cause malignant plasma cell neoplasms in mice treated with chemical carcinogens, s'(97 Unlike Mo-MuLV, Ab-MuLV is able to transform fibroblasts ~'~ and lymphoid cells sJ~,s~9,6~ in vitro. Myeloid leukemias are produced by Graffi virus, S~ansly/Soule myeloproliferative virus, myeloid leukemia virus, and, in mice which have undergone thymectomy in the neonatal period, by the Gross passage-A ~3~ and Moloney "Is strains of MuLV. With each of these viruses, leukemia usually develops after a latent period of at least 3 months. Several isolates of Graffi virus were obtained from mice which had been inoculated with cells or cell-free extracts from various transplantable routine tumors. ~'~'2z' The Stansly/Soule myeloproliferative virus was isolated from BALB/c mice inoculated with ceils or ceil-free extracts of the Ehrlich ascites mouse tumor. ''~ Myetoid leukemia virus was obtained by in vivo passage of an FV-P strain of Friend virus in C57BL and Swiss mice. 3~ No spleen focus-forming activity is present in myeloid leukemia virus stocks, suggesting that F-SFFV was lost during the in vivo passages. The mink celt focus-inducing (MCF) viruses constitute a class of viruses which were originally isolated from the thymuses of preleukemic or leukemic mice of the AKR strain) '~ These viruses are named for their abilit~r to infect and induce cytopathic abnormalities in cultured mink lung cell monolayers. 2so MCP viruses are commonly present in leukemic cells infected with the Friend, Rauscher, Akv, or Moloney strains of MuLV. i~l.l,J,]]2.]s~.6Jg.67s.~76.6,.~l= They have been implicated as the sole etiologic agent or as a coearcirtogen in thymie neoplasms, erythroieukemia, B-cell lymphomas, and spontaneous or chemically induced plasma cell neoplasms. ~'r~'~r'z~r'6~~ One nonleukemogenic MCF isolate can prevent the development of spontaneous thymic leukemias and lymphomas caused by exogenous infection with a leukemogenic MCF strain.'~' Radiation leukemia virus was originally isolated from several strains of mice which had developed thymic leukemias or lymphomas, myeloid leukemias, or bone tumors after receiving X-irradiation. its | 923~ '36:1 Numerous radiation leukemia virus strains have now been isolated. A replication-defective strain, which may represent an acutely transforming variant, was isolated from stocks of highly passaged radiation leukemia virus. 3B" The pathogenetie mechanisms employed by this defective virus and other strains of radiation leukemia virus remain poorly understood. Finally, a unique group of endogenous retroviruses isolated from wild mice captured in California by Gardner et al. ',t" produces a neuro]ogir disorder as well as lymphomas in chronically viremic mice. The neurologic disorder consists of paralysis of the hind limbs and is attributed to the demyelination of motor neurons in the anterior horn of the spinal cord and destruction of cerebellar glial ~lls. Hind-limb paraplegia is also produced by a temperature-sensitive Mo.MuLV mutant. 3~s

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Table 2 HOST RANGE SPECIFICITY OF REPLICATION COMPETENT MURINE LEUKEM'IA VIRUSES Viral tropism" Eeotroptsm Xenotropism Poly or dual-tropism Amphotropism

~pecies permissivefor viral Xtnfectionand replication Murine only Nonrnurineonly Murine and nonmurine Murine and nonraurine

From Levyel. ai., Ref. 358-360. B. Classification by CdbTropism Viral host range is determined by cellular and vira| genetic factors and is itself a critical determinant of the susceptibility of an animal to viru:~-induced leukemia. These concepts are important in understanding the molecular basis of leukemogenesis. The establishment of a retrovirus infection begins with the adherent.*, and adsorption of the virus to the cell membrane, followed by penetration of the virus into the cell. These events are mediated by specific cell-surface receptors for the glyeoproteins of the viral envelope. The molecular biology of these receptors and their interaction with the ~:iral envelope glycoproteins is just beginning to be understood. '2',2~~176176 However, the specificity of this interaction forms the basis of the widely accepted hostrange classificatio~l scheme first proposed by Levy~5~~60(Table 2). According to Levy's definitions, an ecotropic virus is one which can be propagated in cells of the species from which it was original/), isolated. A xenotropic virus, on the other hand, can be propagated efficiently only in calls of species other than the one from which it was isolated. Experimental mixed infections of routine fibrobtast ceil lines have demonstrated cross-interference among all ecotropic strajr~s of MuLV tested, s~,s~ This result suggests that all of these virus strains interact with the same cell-surface receptors. With the exception of a few cell lines established from wild mice, the plasma membranes of murine cells do not contain receptors for the envelope glycoproteins of xenotropic MuLVs. Thus, the inability of xenotropic MuLVs to complete a replicative cycle in murine cells may reflect a receptor-mediated block to the establishment of infection. Xenotropic viruses are infectious in a wide range of species. However, they are generally not pathogenic to the species in which they replicate. Most endogenous viruses are xenotropic. Recombination between an ecotropic and a xenotropie virus may produce progeny v/ruses which can attach to ceU-snrface receptors characteristic of the species from which the parental viruses were isolated, as well as with receptors found in hetcrologous species. 2~ These recombinant progeny viruses can therefore infect cr of both their natural host species and other species. Such viruses are termed polytropic or dualtropic. Polytropic viruses may arise by spontaneous genetic recombination in vivo, or may be constructed in the laboratory using recombinant DNA techniques. The proviral DNA of polytropic viruses or subgenomic fragments of their proviral DNA can be transmitted in the germ line of some strains or mice. These endogenous polytropic viral sequences may recombine with exogenous ecotropic viruses to generate recombinant polytropic viruses. '2 The final category consists of the amphotropir viruses, which, like the polytropes, can replicate in both homologous and hetcrologous species. In contrast to polytropic viruses, however, amphotropie viruses po~ess envelope glycoproteins which are anti-

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Non-~efective U3RU5 Avian Sarcoma [ ~ Viruses

GAG POL ENV ....................

Non.delective U3RU5 GAG Murine Leukemia~ .......... Viruses

POL

SRC

U3RU5

ENV U3RU5 -- - --

FIGURE 2. Schematicrepresentationof the proviral genomesof nondelrectivcASVs and nondefectire MuLes. genically dissimilar to those of ecotropic and xenotropic viruses. 58.z',.5~ Interference assays have demonstrated that the cell-surface receptors for the envelope glycoproteins of the amphotropic viruses are different from the receptors which bind the envelope glycoproteins of the ecotropic or xenotropic MuLVs. ss,~*,'st3 Unlike MCF viruses, am. photropic MuLVs do not cause cytopathic changes in cultured mink lung cells. Marry amphotropic MuLVs are only weakly pathogenic. At least one isolate has been re. ported to be n~npathogenic in certain strains of mice. The MuLVs most frequently used in leukemia research include the Molo;ley, Friend, Rauscher, and SL3-3 strains. All of these isolates are ecotropic viruses and can replicate only in mouse or rat ceils. Xenotropic endogenous viruses or virus-specific sequences have been detected by nucleic acid hybridization analysis within the genomes of all inbred and wild mouse strains tested. Endogenous viruses can be cloned by use of recombinant DNA techniques and transfected or microinjected into cultured cells for assays of host range. Such assays demonstrate that the majority of endogenous routine retroviruses are xenotropic and can be propagated in cells of heterologous species, but not in mouse cells. The Friend and Rauscher SFFVs are defective viruses that do not contribute glycoproteins to the viral envelope, therefore, these viruses exhibit the tropism of the replication-competent helper viruses present in all isolates of SFFV. The MCF viruses are polytropic viruses and thus can be propagated in routine cells and in cells of heterologous species. The isolation of a variety of ecotropic, xenotropic, and MCF radiation leukemia virus strains has been reported. ,,~-,i,.~,.=38.23, Ecotropic MuLVs can be further subdivided into N-tropic, B-tropic, and NB-tropic groups, depending on their ability to replicate efficiently in NIH Swiss (N), BALB/c (B), or both (NB) of these types of mouse cells."' Genetic evidence suggests that Btropic MuLVs are produced by recombination between N-tropic viruses and endogenous ecotropir or xenotropic viral sequences. ~'-~'2~ All NB-tropic viruses have arisen by forced passage of B-tropic parental viruses in N.type cells. The Moioney, Friend, Raus~:her, and SL3-3 MuLVs are all NB-tropic. The MCF viruses also exhibit N- or B-tropism" the tropism of a given isolate is determined by that of its ecotropic parental virus. Certain MuLV isolates from wild mice of the species Mus musculusare the only known amphotropic viruses. These viruses characteristically exhibit N-tropism with respect to growth in cultured murine cells. C. Classification by Molecular Genetics 1. General Structure of the Retrov/rus Genuine The genorne of the nondefective retroviruses, such as the ASVs (Figure 2), consists of a single-stranded RNA molecule which sediments at 35S on neutral sucrose gradients. ~'''*,'*e The genomic 35S RNA molecule has a tool wt of 3.4 x l0 ~ daltons, as determined by sedimentation equilibrium ultracentrifugatiort and agarose gel electrophoresis. 3'7,~=2This tool Wt corresponds to a length of 9 to 10 kbases and a maximum

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protein-coding capacity of approximately 3,4 • l0 s daltons. The genomic RNA of all of the retroviruses possesses messenger polarity, as indicated by the presence of a 5'terminal methyl "cap", 4a.~gs'3~9,~'."''~' methylation of certain internal adenylate residues,".l~4.1~*.64t and polyadeny!ation of the 3' terminus,21 ~,2~.,29.s,~.~3~.,~ The retroviral genome is diploid. Two iderttJca135S RNA molecules are linked within the virions of the retroviruses by base pairing between their 5' termini. ~r-~176 The virion RNA species sediments at 60-70S on neutral sucrose gradients, m'~'s~4 The two subunits of 35S RNA may be generated during denaturation of the 60-70S virion RNA species by heatilig at 65~ or by treatment with dimethyl sulfoxide. ~9.'~'420 Denaturation of the 60.70S RNA also releases a number of 4-7S RNA molecules, which are associated with the large dimer in the virion. '''tss'~'~" However, one molecule of 4-5S tRNA remains bound near the 5' terminus of each 35S RNA subunit even after the 6070S RNA species has been heat-denatured at 65~ This remaining tRNA molecule is the initiation primer for reverse transcription. Oligonueleotide mapping and molecular hybridization analysis of the genomic RNA of various wild-type and mutant retrovirus strains have established that the genome of the nondefeetive ASVs contains four distinct genes, a~,*~176176 7~9.~4 Starting at the 5' end of the 35S RNA molecule, near the methylated "cap," and proceeding toward the polyadenylated 3' terminus, these are the gag, pol, env, and arc genes, encoding, respectively, the internal structural proteins of the virion, the reverse transcriptase polypeptides, the envelope glycoproteins, and the oncogene product. The oncogene product, or "src protein", is a 60,000-dalton phosphoprt~tein with tyrositae kinase activity?S.9~.,~,.2,7.~oo.so, Sequence analysis of the terminal regions of the genomes of various retroviruses has demonstrated the presence of a short polynucieotide sequence which is repeated at both the 5" and 3' termini. ~''92'25~'~r This redundant or " R " sequence is believed to function in the transfer of the first strand of newly synthesized viral DNA from the 5' to the 3' end of the template RNA strand early in reverse transcription. The R region of the MuLV genome also contains nucleotide sequences which act as signals for polyadenylation. ~~ The R sequence is separated from the binding site for the tRNA primer by a highly conserved, nonreiterated portion of the genome known as the Us regioll. ~~176176 The U~ region is therefore the first portion of the vira~ genpine to be reverse-transcribed. On its 3' side, the primer binding site is separated from the first codon of the gag gene by an untranslated leader sequence (L region).ta ~.~4o,47~.~rr.~o~.~s~.~s~ At the opposite end of the genome, another highly conserved, nonreiterated sequence, the U~ region, separates the 3' end of the coding sequences of the env gene or the viral oncogene from the 3" R sequence and ttte 3'-terminal polyadenylate t~act, s~.~',a~.~*~,*s'.~,ss',~s~,~'7.~ts,''''''" The U~ region encodes the promoter for virusspecific RNA synthesis and contains nur sequences which may represent signals for polyadenylation in the avian retrovirusess'' an~t possibly for initiation of reverse transcription and recognition for integration of the provirus. Recently, transcriptionenhancer sequences in the form of tandem repeats have also been found in the U~ region of the Mo-MSV genome: ~''~r 2. Oenomes o f the Replication-De[ectJ've Acutely Transforming Retroviruses Unlike the avian sarcoma viruses, most acutely transforming retroviruses are repli. cation-defective. The replication-defective acutely transforming retroviruses include the sdrcoma viruses of mice and other mammals, in general, the genomes of the replication-defective acutely transforming viruses are smaller than those of the nondefeetive viruses because of the deletion of variable portions of the gaS, pol, and/or env genes, all of which encode polypeptidr required for virus replication. Transforming eapabil-

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ity is conferred upon these viruses by the presence of oncogenic cellular DNA sequences or oncogenes. 23 The genome of each type of replication-defective acutely transforming retrovirus (for example, AMV and the various strains of MSV) possesses a specific oncogenic sequence analogous to the src gene of the nondefeetive ASVs. Stehelin et al. ~ were the first to employ reverse transcriptase to synthesize radioactively labeled DNA probes complementary to viral oncogene sequences. These investigators identified the src.specific sequences by using RNA from nondefecfiw ASVs and from transformation-defective ASV mutants bearing src gene deletions as alternate templates for complementary DNA (eDNA) synthesis. Molecular hybridization analysis using such eDNA probes for oncogene-re/ated sequences has demonstrated the presence of unique DNA and RNA sequences related to src in uninfected chicken cells, '~.6~'~'~-~ More recently, recombinant DNA techniques have increased the sensitivity of this analysis, permitting the identification of DNA or RNA sequences related to src or to several other oncogenes in uninfected ceils of Drosophila melanogaster and all of the vertebrate species tested, including h u m a n s , s'~'to~'tt('t2~ tBg, 214,~,B.$93,500,(i13,,0(.~'29.747,754 Many cellular oncogenes have been mapped to specific chromosomes or chromosomal loci within the genomes of humans, mice, chickens, and certain other species. The high degree of evolutionary conservation of cellular oncogenes, and their expression in normal, uninfected cells, strongly suggest that these genes participate in normal cellular processes, perhaps helping to regulate cell proliferation and differentiation, sR2 If so, alteration in the expression of cellular oncogenes could be responsible for at least some instances of carcinogenesis. '''96'~3a'34~

3. General Structure of the Murine Leukemia Virus Oenome The leukemia viruses of mice and other mammals are replication-competent retro. viruses which cause a wide variety of hematologic maligna,~cies in rico, but are unable to transform fibroblasts in vitro. Their genomes contain functional gag, pol, and env genes as well as the terminal redundanl: sequences (Figure 2). However, these viruses do not contain oncogenes. Consequently, the genomes of the mammalian leukemia viruses, like those of the replication-defective transforming viruses, are smaller than the genomes of the nondefective ASV strains. The genomes of the Moloney'a* and Akv as~ strains of MuLV have been completely sequenced and are approximately 8.3 kbases in length. The polypeptide constituents of various wild-type and mutant MuLV strains have been identified and characterized as to size, structure, chemical and antigenic properties, and function. Most studies of MuLu polypeptides have utilized sodium dodeeyl sulfate - - polyacrylamide gel electrophoresis or gel filtration to separate the virion pr(~teins and to establish the tool wt of the simple virion polypeptides (designated by the letter "p'" followed by the tool wt in thousands of da)tons and a superscript indicating the gene of origin) and the viral glycoproteins or phosphoprotei~s (designated by " g p " or " p p " followed by the symbols for their tool wt and gene of origin). '2 The virion proteins of the MuLVs include products of the viva! gag, pol, and eat' genes. Encoded by the gag gene are the internal structural proteins of the virion: p30 (the major structural protein), plS, pot2 (the principal viri0n phosphoprotein, ('~ with RNA-binding activity specific for tire homologous virion RNA molecule, s's~'') and p l0 (an RNA- and single-stranded DNA-binding protein). '~ The pol gene encodes the virion reverse transcriptase molecule, which, together with the sagproteins, is complexed with the viral RNA genome in the virion core. 4T'J~s The env genr encodes a nonglycosylated envelope protein, p I5(F_,)as~ as well as the major.virion glycoprotein, gpT0. Sodium dodecyl sulfate -- polyacrylamide gel electrophoresis of virus-specific proteins immunoprecipitated from infected cells or from cell-free translation systems has

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been used to analyze the synthesis and processing of MuLV proteins. Such methods have demonstrated that the primary tram]ation product of the MuLV gag and po! genes is a 180,000-dalton polyprotein, designated Pr (for precursor) 180~,s-~,z.9.~0.,~.3aa.a4~.,,6.,~.,a~.43s.,~o.-s After incorporation into virions, Pr180 , ~ undergoes processing by a complex series of proteoiytic cleavages and glycosylation and phosphorylation events to yield the internal structural proteins of the virion (gag gene products) and the viral reverse transcriptase (po/gene product). A number of short-lived polypeptide intermediates are generated during processing of Prl80 c~ and are themselves rapidly processed to yield other precursors or the mature gag and ~=,,~.~,,.,s,~,~,.,~.,s.~s~ The ellzy~es responsible for the post-translational processittg of Prig0 ~a-'~ in vivo have not been identified. Although processing occurs in budding viral particles after the initial stages of virion assembly have been completed, "',''~,'s~ neither Prlg0 '~ nor the polypeptide intermediates are detectable in mature virions. Several methods have been employed for intracistronir mapping of the MuLV gag gene. These include analyses of the amino- and r amino acid sequences of the murine retrovirus gao~gent prociucts, '~, tryptic peptide mapping of the intermediates in the post-translational processing of Prl80~,,-~*,4~* and studies of gag gene expression at the nonpermissive temperature in cells nonproductively infected with various strains of the replication-defective MSVs. ~'sta Together, these approaches have established the order in which the MuLV internal structural proteins are encoded by the gag gene as 5'-plS-pp12-p30-p10-3'. A glycosylated common precursor to gp70 and plS(E) has been detected by immunochemical methods in virus-infected cells and in cell-free translation systems.~O.,s~,,~-~~ This ~recursor has a mot wt of 80,000 to 90,000 daltons, depending on the strain of MuLV. lntracistronic mapping of the e~v gene using the antibiotic pactamycin, which, over a limited range of concentrations, inhibits the initiation of translation, but not elongation of previously initiated polypeptide chai~s, has indicated t~at gp70 .~ encoded by tb,e 5' portion of the gene, and p t 5(E) by the 3' portion. ~ Mature virions possess an envelope protein complex consisting of gp70 and p IS(E) molecules covalently linked by disulfide bonds. ~*s'4~t'*9~'**s',3* The adsorption of MuLVs to cell membranes at the outset of infection is mediated by interaction between gp70 and specific cell-surface receptors; TM gp70 is therefore an important determinant of the host range of the MuLVs. This concept is important to our understanding of the molecular basis of routine viral leukemogenesis and will be discussed further below (see Viral. Genetic Determinants of Lcukemogenir 4. Variations in Genome Structure among Different Murine Leukemia Virus Strains While most MuLVs share common features of genome structure and expression, ce~'tain strains have unique genetic properties. Ab-MuLV was derived by passage of Mo-MuLV in a mouse which had been treated with prednisolone to induce chemical thymectomy. ',2 The genome of Ab-MuLV is smaller than that of the Moloney strain, measuring approximately 5.6 kbases, sos The Ab-MuLV genome has been completely sequenced? '= The 5'- (1320 bases) and 3'- (730 bases) sequences of the genomr of MoMuLV are preserved in Ab-MuLV,'" but the central portion of the Ab-MuLV genome is related to a cellular gene, u'z, The Ab-MuLV genome encodes a polyprotein with a tool wt of 85,000 to 160,000 daltons, depending on the precise strain of virus. ~s-s''.'~.~'~.7~ This poiyvrotein cross-reacts with the interrtal virion proteins plS*" and ppl2", and with the amino-terminal portion of p 3 0 " ' ? ' " " Thus, Ab-MuLV is believed to have arisen by recombination between Mo-MuLV proviral DNA and cellular DNA. The recombination event joined the Mo~ gag-specific sequences to

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cellular sequences encoding the c-ablgenr The gag-abIpolyprotein possesses tyrosine kinase activity, s~~'7~'7~7The pl60 ''''~t and p120 ''~bt polyptoteins have greater kinase activity and are more highly oncogenic in mice than the smaller gag-abl gene products of other Ai~elson virus variants. 21s's'Q's'~'~, The genome of the Friend strain of murine leukemia virus (F-MuLV) closely resembles that of the Moloney strain in size and general structure. However, the replicationdefective SFFV component of Friend virus stocks has a smaller (approximately 6.0 kbases) genome whose sequences have been shown by molecular hybridization analysis, 29,42.~.~7'.~n heteroduplex mapping, 5~a~uoligonucleotide mapping, ~~ and nucleotide sequence analysis "'~'3'7'' to be derived by recombination between F-MuLV and either polytropic MCF virus strains or endogenous xenotropic viral sequences. These studies have also demonstrated that the genorne of the SFFV component of FV-P differs from that of the corresponding Friend MCF virus strain by virtue of one deletion within the e~v gene and another deletion involving portions of the gag and pol genes. The resulting truncated ear gone encodes a 52,000-dalton giycoprotein which is structurally re~ated to the envelope glycoproteins of polytropic MuLVs. '-9.''~,~B.so4.~s.~74'7~.7*s,755 The polycythemia- (F.SFFVj,) and anemia- (FSFFVA) associated strains of F-SFFV differ in the structure of their envgenes, as demonstrated by oligortucleotide tnapl~ing '6~ and comparative tryptic peptide analysis of the corresponding gp52"" glycoproteins. 3~ Sequencing of cloned viral DNA has demonstrated additional structural differences within the ptS(E)-cod~ng regions of the env genes of the two strains of F-SFFV. TM The strains also differ in the quantity of gagspecific information present in their genomes: F-SFFV~ encodes the internal virion proteins p15 '~ ppl2 '~ and p30'", ~7~ while variants of F-SFFV,, encode p15 ~~ and ppl2 '~ pl$'~ ' alone, or no ~ag.specific polypeptides at all. ~*,'~ The SFFV associated with Rauscher leukemia virus also has a defective envgene, ~' which encodes a 54,000dalton glycoprotein. ~-'~'~: The ~ag and poI genes of Rauscher SFFV are intact, s~'~ The MCF viruses were initially characterized on a genetic basis by the antigenic cross-reactivity of their gpT0~ envelope glycoproteins with those of both ecotropic and xenotropic MuLVs. ~~ This early discovery suggested that MCF viruses arose by recombination between ccotropic and xenotropic parental virus strains. Tryptic peptide analyses of the envelope glycoproteins of MCF viruses and various ecotropic and xenotropic MuLVs, ~s~ cross-reactivity studies of the envelope glycoproteins with monoc|onal antibodies, ~ ' " " heteroduplexs~ and oligonucleotide ~*~'a=''s~'ss~ mapping of the viral RNA genome, and restriction mapping of integrated MCF proviruses ~=.'" have identified the parental r virus of several MCF virus isolates. In no case, however, has the l~atental xenotropic virus been clearly identified. These studies have confirmed that MCF viruses arise by recombination within the env genes of the I~arental viruses. A second recombinant site has been identified by assays of immunologic cross-reactivity and by comparative tryptic peptide analysis. This site is within the ppl2-coding re$ion of the $ag gene6~' of a myeloma-associated MCF virus strain. ~o Like the MCF viruses, amphotropic MuLes exhibit a polytropic host range. However, the envelope 81ycoprotcins of amphotropic MuLVs are antigenieally distinct from those of r and xenotropic strains, s~'~~ The amphotropic viruses do share group-specific antigenic determinants with other MuLVs. a'~ Oii8onucleotide mapping has demonstrated a number of sequence differences among different strains of amphotropic MuLVs, as well as between amphotropic and other MuLVs. ~''s's~ Structural polymorphism in the $p70 "~" envelope glycoproteiris of amphotropic viruses has also been demonstrated by tryptic peptide analysis s' and radioimmunoassay. ~

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IV. N A T U R A L HISTORY OF M U R I N E VIRAL LEUKEMIAS The rauriae leukemia viruses induce a broad spectrum of hematopeietir malignancies. For a detailed discussion of the patholt~gy of murine leukemias, the reader is referred to the excellent review by Gross. ~3. The various strains of inbred mice used in laboratory research vary widely in their susceptibility to "spontaneous" leukemia. The strain.specific incidence ranges from ! to greater than 90~ ~2.zJs.~'~ and the medial~ age at onset of disease varies from 6 to 24 months. The incidence of leukemia in many strahas of laboratory mice can be increased by exposing animals to X-irradiation or chemical carcinogens, which activate latent endogenous proviruses. Three modes of transmission of retrovirus infections are recognized: (l) horizontal, by postnatal exogenous infection; (2) vertical, by irtheritance of proviral DNA sequences stably integrated in the routine genomr and (3} vertical, by trans-uterine in. fection during birth, (i.e., congenital exogenous infection rather that, true genetic transmission). Although MuLVs can be transmitted from infected females to their progeny via the milk, few newborn mice develop leukemia as a result of infection by this route. In contrast, lactation is an important mode of transmission of routine viral mammary carcinomas. Genetic transmission underlies most cases of viral leukemia in the inbred mouse strains used in laboratory research, while exogenous infection predominates in wild mice ~nzooticallv infected ,~ith amphotropic MuL',r s. ~ Regardless of the mode of transmission, persistent or chronic viremia usually precedes the appearance of leukemia. The clonal origin of vitally induced routine hematopoietic malignancies has been controversial. Restriction mapping has demonstrated that proviral DNA sequences of thymotropic MuLVs are integrated into the genome of mice with thymic malignancies at the same loci in every cell. ~176 This finding suggests that these neoplasms are indeed clonal in origin. Specific integration sites for SFFV proviruses have been detected in the malignant cells of mice with Friend erythroleukemia, but not in infected, preraalignant cells from the same animals. '~ Thus, the early manifestations of erythroleukemia in Friend virus-infected mice almost certainly reflect the simultaneous infection of tnar~y different ceils rather than a clonai proliferati'~r process. **'-6~ The hematopoietic malignancies caused by infectious ecotropie MuLVs such as the Gross passage-A strain 23" or the Moloney strai# '~'('7 includes thymic leukemia, disseminated lymphosarcoma, or lymphocytic leukemia with hepatosplenomegaly. The latent period for the emergence of these disorders after exogenous infection is generally 10 to 12 weeks. Naturally occurring infection of murine embryos with ecotropic MuLVs has been flemonstrated, ss' and is a prognostic factor for the subsequent development of thymic neoplasms during the neonatal period. In fact, the overall incidence of leukemia for most inbred mouse strains is correlated with the strain-specific prevalence of ecotropic virus infection during embryonic development. ~4*'*~t'sst Typically, the earliest histologic evidence of disease is found in the thymus. Later, leukemic cells can be identified in the spleen, bone marrow, and periphera! blood. Involvement of the thymus alone, prior to the emergence of leukemic cells in the blood or bone marrow, is referred to as the prdeukemic phasr of the disease. The late portion of the preleukemic phase, which generaUy occurs after 5 months of age, is characterized by the expression of MuLV-specific antigens on the surface of thymocytes, and by the appearance of infectious and Usuall~ ieukemogenic recombinant MCF viruses. '~176 A characteristic karyotypic abnormality, trisomy of the distal region of chromosome 15, is associated with routine thymic malignancies. The trisomy is found it~ thymir leukemias and lymphomas induced by X-irradiation or chemical carcinogens, as well as by genetic transmission of leukemogenic proviruses or exogenous infection with ecotropir

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or polytropic MuLVs. t~9'~s''~'~'6tg''3~73, It is unclear whether the trisomy is directly involved in the etiology of murine leukemia or is a secondary manifestation or marker of the leukemogenic process. However, the c-myconcogene has been mapped to mouse chromosome I~, ~>~,ss9suggesting that altered expression of this cellular oncogene may play a role in the pathogenesis of thymic malignancies (see Insertional Mutagenesis and the Promoter Insertion Hypothesis). The erythroleukemia produced by Friend virus is characterized by increased numbers of proerythroblasts in the bone marrow, circulating proerythroblasts, hepatosplenomegaly, and either anemia ~9' or polycythemi# ~176176176 depending on the strain of SFFV present in a given Friend virus isolate. The proliferation of erythroid precursors is greatly accelerated in both the anemic and polycythemic forms of Friend erythroleukemia, although, by definition, the hematocrit is abnormally low in anemic erythroleukemia and abnormally high in the polycythemic form. The anemic and polycythemic forms of Friend erythroleukemia reflect two distinct mechanisms of virus.induced pertttrbation of erythroid stem cell proliferation and differentiation. Erythropoiesis retains its responsiveness to endogenous or exogenous erythropoietin in the anemic form of Friend virus disease, but the regulatory influence of erythropoietin is lost in the polycythemic variant. 4~176 In both forms of the disease, the manifestations of erythroleukemia occur within a few days after infection of adult mice; the comparatively short disease latcncy is another reflection of the lcukemogenic potential of the SFFV component. The F-MuLV hetper viruses present in tile FV-A and FV-P isolates are themselves capablc of producing thymic t'~ and mycloid 77.sp~ leukemias as well as erythroleukemia 377 .4,~7.~75 in neonatal mice. F-MuLV can also ~.nduce erythroteukemia after a prolonged latent period in adult mice which have been subjected to neonatal thymectomy, X-irradiation, or treatment with phcnylhydrazine or silica. ~ti,~5' Studies of the in vivo and in vitro growth properties of the leukemic cells have led to the identification of at least two distinct stages of Friend erythroleukemia. The erythroleukemia produced by one strain of Friend virus (the regressor strain) is subject to spontaneous remission, 5~~which appears to be mediated by macrophages. ~a9'39~Susceptibility to spontaneous remission is apparently a property of the F-MuLV helper and not of the associated SFFV. ~3 The natural history and hematologic manifestations of Rauscher virus disease are similar to those induced by the FV-A. Within 14 days after exposure to the Rauscher leukemia virus, neonatal or adult mice develop erythroleukemia characterized by anemia, hepatosplenomegaly, and the presence of proerythroblasts in the peripheral blood and in excessive numbers in the bone marrow. Evolution to acute lymphoblastic leukemia occurs after several weeks in surviving animals. ~,~~ The acute and chronic stages of Rauscher virus disease correlate with the presence of tlte SFFV component and the replication-competent Rauscher MuLV helper, respectively. 2.3"~* Isolates of the MCF viruses purified from Rauscher virus stocks are themselves able to induce erythroleukcmia in newborn mice with a disease latency of 3 to 6 months. .9) Numerous MuLV strains other than Friend virus (e.g., Graffi virus, Stansly/Souie myeloid leukemia virus, myeloproliferative sarcoma virus, and certain strains of radiation leukemia virus) are also capable of inducing myeloid leukemias. Neonatal thymectomy renders some mice susceptible to the induction of myeloid leukemias by the Gross passage-A 23~ or Moloney4~a strain of MuLV. These myeloid leukemias are characterized by the presence of marked leukocytosis {generally greater than 100,000/trim2)), circulating myeloblasts, increased numbers of myeloblasts and other immatur, granulocyte precursors in the bone marrow, and variable involvement ~f the lymph nodes (chloroleukemia or granulocytic sarcoma), sl)l~n, liver, lungs, thymus, and other organs. 2~,2J).''.((~,6,2.~a~ Lymphadenopathy and hepatosplenomegaly are often the first signs of routine r. . leukemia and may be massive, Myeioid leukr usually does .

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not develop until 3 to 6 months after infection of newborn mice; the latent period is longer for adult mice. The pre-B cell lymphoproliferative disorder induced by Ab-MuLV occurs within 4 weeks after inoculation of newborn or adult BALB/c mice ~'2"~''~176 or athymic nude mice. ~~ This disease is characterized by early involvement of bone marrow and lymphoid tissue. Secondary invasion of cortical bone and soft tissue adjacent to hematopoietlcally active bone marrow accounts for the different anatomic patterns of bulky disease observed in newborn and adult mice, reflecting the age-related changes in the distribution of active marrow. Involvement of the thymus is uncommon and appears microscopically to represent infiltration of the gland by blood-borne tumor cells, rather than primary neoplastic proliferation of thymic tissue as in the thymie leukemias and lymphomas? ~ The identification of ore-B lymphocytes as the target cell population for Abetson virus-induced leukemia is based on the morphologic features of the malignant cells5~176 and on studies of their expression of cytoplasmic and cell-surface immunoglob ulins. 49.~gs.~9.s~,,.~6~.006.609,6|O.6~0 Ecotropic and amphotropic MuLVs isolated from certain strains of wild mice indigenous to California 7"x~ produce lymphoma and a neurologic disorder when congenitally infected mice reach maturity. Amphotropir virus strains are much more prevalent than ecotropic strains among these wild mouse l~opulations. Infection is trar~smitted primarily through the milk, beginning shortly after birth, and chronic viremia is be~ieve~i to result from immunologic tolerance induced by neonatal exposure. '''z~* Both ecotropic and amphotropic isolates of these viruses are associated with the development of lymphomas, which usually spare the thymus. The latent period for lymphomagenesis following infection of newborn inbred mice is 18 to 24 months for amphotropic isolates, compared to approximately 10 months for ecotropic virus strains. ~7.s08 in contrast, the latent period for emergence of the neurologic disorder is approximately 3 months. 4s3,4ss V. HOST AND C E L L U L A R D E T E R M I N A N T S OF LEUKEMOGENESIS A. Physiolo$ic Factors The demonstration by Gross that leukemia could be transmitted by cell-free extracts of leukemic cells established the viral etiology of routine leukemia. Gross found that transmission of leukemia was dependent upon the use of newborn rather than older mice as recipients of the cell-free extracts. 2=sTwo explanations for the requirement for the use of newborn animals have been offered: (l) the immature immune systems of newborns may render them more susceptible to infection; (2) the relatively high growth fraction of the hematopoietic stem cells of newborn mice may favor the development of leukemia once infection has been established. Even before Gross reported his initial observations, a number of other physiologic determinants of the susceptibility of mice to viral leukemogenesis were identified. The early recognition that female mice of high-incidence strains were more likely to develop leukemia than males of the same strain, and exhibited a shorter disease latency, led to studies of the effects on leukemogenesis of experimental manipulations of the endocrine system. These investigations demonstrated that castration of males'~6,42. and administration of exogenous estrogens to mice of either sex 2~ increased the incidence of leukemia. Oophorectomy or testosterone administration reduced the risk of leukemia among females? "a The incidence of "spontaneous" thymic leukemias and lymphomas is decreased by surgical or chemical ablation of the thymus. The same is true for thymic neoplasms induced by X-irradiation or exogenous virual infection. 2~2,~~ The prophylactic effect of thymectomy has been attributed to the elimination of the preferred target-cell population for the replication of MuLV strains

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Table 3 Fv-1 GENOTYPE VERSUS THE RELATIVE EFFICIENCY OF MURINE LEUKEMIA "r REPLICATION IN CULTURED FIBROBLASTS _

_

Viral genot?pe _ . . . . . . . .

Muritte gcnotype

N-tropic

B.tropic

/:r

+++

+

NB-tropic +++

F~,./t~

+

+++

+++

Fv-P"

+

+

+++

(e.g., Gross passage-A and Moloney) which cause thymic malignancies. This conclusion is supported by the finding that transplantation of allogeneic thymic tissue j~ or bone marrow ~~ into thymeetomJzed mice increases their susceptibility to hematologic malignancies. Thymectomized mice are more likely than normal animals to develop myeloid leukemias after exogenous viral infection, '''.''~ Thymectomized animals also exhibit a higher incidence of non-T-cell lymphoid neoplasms after exposure to radiation, while the incidence of radiation-associated myeloid leukemias is approximately the same in thymectomized and normal mice. ~'" The effect of target-tissue ablation has also been illustrated by the discovery that the incidence of erythroleukemia and myeloid leukemias following exogenous viral infection or irradiation is decreased by splenectomy.'* Splenectomized animals are more prone than others to develop nonthymic lymphoid malignancies, but the incidence of thymic disease is not altered by removal of the spleen. B. Host Resistance Genetics Interaction between retroviral envelope glycoproteins and specific cell-surface receptors for these glycoproteins is required for the establishment of a retrovirus infection. The specificity of this interaction determines the species and strains of animals which can be infected by a given retrovirus. However, certain cellular genetic mechanisms are capable of restricting the replication of retroviruses after penetration of the ceil membrane is achieved. These postpenetration restriction mechanisms are also important determinants of viral host range. Susceptibility (permissiveness) or resistance to the intracetlular replication of various ecotropic MuLVs is regulated by a single locus (Fv-1)in the cellular genome of all inbred mouse strains, s66.'~'.'9~ The Fv-I gene has also been found to be one of several genetic determinants of susceptibility to Friend erythroleukemia in vivo. ~'',3''.~ The two alleles which have been characterized for this locus, Fv-P and Fv-I', reflect the genetic relationship of a given animal to BALB/c (b) and NIH Swiss (n) mice. These alleles determine, in a Mendelian autosomal dominant manner, the susceptibility of inbred mice (or cultured cells derived from them) to the replication of B-tropic and N-tropic MuLVs, respectively2.~ (Table 3). Thus, B-tropic MuLVs are able to replicate efficiently in cultured cells derived from mice with the Fv-I ~* genotype, while N-tropic MuLVs can be propagated in cells from Fr-P" mice. Neither B-tropic nor N-tropic MuLes can replicate efficiently in ceils from mice with the opposite homozygous genotype or with the heterozygous Fv-I '~ genotype. Under these circumstances, virus replication is said to be restricted. However, NB-tropic MuLV strains can replicate equaUy well in Fr-/~ cells and in cells from Fv-P" or Fv-l" mice. Cells'derived from several strains of wild mice or random-br~ labo/'atory mice are unable to restrict the replication of ecotropic MuLVs. The genotype of such cells is designated Fr..I "~'. The resist-

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ance or susceptibility to intracellular virus replication which is conferred by the Fv.l locus is not absolute. Replication can still occur, albeit inefficiently, in cells with a nonpermissive genotype, and high multiplicities of infection can overwhelm the Fv-l. mediated restriction mechanism altogether. ''~'''~'~ The mechanism of restriction of virus replication which is mediated by the Fv-I genetic locus involves a reciprocal interaction between the viral and cellular genomes. The mechanism of Fv-l-medJated restriction is unrelated to the interaction between the viral envelope glycoproteins and their cell-surface receptors, which determines viral host range. Efforts to elucidate the Fv-1 restriction mechanism have been complicated by the discovery that N-tropic viruses can be isolated from ostensibly nonpermissive ceils. Thus, N-tropic as well as B-tropic MuLVs have been isolated from mice with the Fv.P b genotype6~.2".4s9'66' and from cultured cells derived from such mice. ~~ In contrast, B-tropic viruses have never been isolated from mice or ceils with either the Fv-P" or Fv-I "~ genotype. It now seems clear that Fv-1 restriction involves inhibition of the synthesis and/or integration of MuLV proviral DNA. Integrated proviral DNA can be detected only in permissively infected cells, and not in infected cells with a resistant Fv-I genotype. Unintegrated viral DNA is present in similar quantities in permissively and nonpermissively infected routine cells? ~3'6" More recently, however, the closed circular fraction of unintegrated viral DNA has been found to be decreased in certain nonpermissive infections. ~gs-~s~-'~2This finding has been attributed to a specific failure of circularizalion of newly synthesized viral DNA. 2~ Thus, the expression of a resistant Fv-I genotype appears to involve the synthesis of viral DNA which is unable to undergo circularization either because of an alteration in the primary structure of the DNA or because of deficiency or impairment of the enzymatic mechanism ordinarily required to process linear duplex DNA for integration. The control of susceptibility to Friend virus-induced erythroleukemia exerted by the Fv.2 murine cellular gene was recognized even before the Fv-I locus was identified."' The Fv-2 locus, which is situated on a different chromosome than Fv-I, restricts the replication of F-SFFV in hematopoietic r j6s The dominant allele encodes permissiveness to replication and susceptibility to r while the recessive allele restricts replication and confers disease resistance. All but one strain of inbred mice are homozygous for the allele conferring susceptibility (Fv-2'~). Only C57BL/6 mice are homozygous for the recessive allele (Fv-2"). The molecular mechanism by which the Fv-2 locus restricts SFFV-induced leukemia is unknown. Both infected hematopoietic ceils and uninfected but susceptible cells contain SFFV-specific RNA sequences ~g' and express a call-surface antigen s~s which are absent from resistant cells. The presence of the virus-specific sequences and the c9 antigen thus correlates with the expression of the susceptibility allele at the Fv.2 locus. The gene al~o regulates the level of DNA synthesis among early erythroid progenitor cells, with a greater proportion of permissive than nonpermissive cells in S-phase at any given time. **s A macromolecule which appears to mediate the effect of the FV-2 locus on erythroid precursor DNA synthesis has l~een identified in the bone marrow of Fv-2" mice. '~ This macromoleeule may represent the Fv-2 gene product. Alternatively, it may be encoded by another gene, and its expression or activity regulated by Fv-2. '~ The Fv-2 locus may thus participate in regulating normal hematopoiesis, as well as in determining the outi:ome of infection with SFFV. Four other host resistance genes of the Fv series have been identified and partially characterized. The Fv-3 locus controls the ability of Friend virus-infected hematopoietic ceils to respond to various mitogens. 325 Resistance to Friend virus-induced discase is conferred by a dominant allele at the F v ~ locus. 84$ .647 This resistance is believed

to result from gene-mediated restriction of helper virus replication, since the Fv-41ocus

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restricts the replication of all ecotropic M u L V s . a~176 The expression of the resistant allele is correlated with the appearance of a cell surface antigen related to the envelope glycoprotein gp70""" of ecotropic MuLVs. TM However, the mechanism by which the gene restricts virus replication remains unknown. The Fv-5 locus determines whether a transitory anemic phase precedes the onset of polycytheraia in C3H or CBA mice after infection with FV-P. ~.6'~9' Infected erythroid progenitc>r cells from animals experiencing the anemic phase proliferate in semisolid culture media with no requirement for erythropoietin. As expected, erythropoietin-independence is preserved when polycytherein supervenes. The Fv.5 gene has been implicated in the physiologic regulation of the proliferation of mature erythroid precursors, ~9' a function which may underlie its influence on the early stage of Friend virus disease in C3H and CBA mice. The gene does not affect permissiveness for virus replication or susceptibility to Friend virus disease per se. The Fv-6 locus controls susceptibility to the rapid induction of erythroleukemia by the helper virus F-MuLV, s96 Long-latency erythroleukemia and other forms of leukemia may still occur in mice with the resistant Fv-6genotype. Expression of the dominant resistance allele at this locus correlates with the intracellular expression of an antigen which is related to the MCF virus envelope glycoprotein gp70""'. 5~3 This finding has led to the hypothesis that restriction of F-MuLV-induced disease by the Fv-6 gene is mediated by inhibition of the recombination events that give rise to the associated pathogenic MCF viruses. Alternatively, the resistance allele may restrict the replication of newly formed MCF viruses. ~5'~ Other murir~e genetic loci also help to determine the susceptibility of an individual animal or strai~t to viral replication and leukemogenesis. For example, the presence of cellular sequences encoding various ecotropic endogenous viruses is an important predictor of both ttae incidence of leukemia (Akvloci) and the spontaneous expression of virus-specific antigens ( Tin and Gv loci) or infectious viral particles (hr, Sty, and Rgv loci). ,'.7,.,'.,~2,s''-s~~ The spotting (W), steel ($1), and flexed tail (f) loci are three independent genes in which mutatiofis give rise to hereditary anemias, sterility, abnormalities of physical appearance, and nonpermissiveness to SFFV replication. ~s-3s.3r~,~.~2~ The mechanism or mechanisms by which these mutant alleles restrict SFFV replication are unknown. The immunologic responses of mice to MuLV antigens or to the altered cell-surface antigens of MuLV-infected ceils are governed by a number of genes, including some which are components of the murine H-2 major histocompatibility complex. For example, the H-2-1inked genes Rfv-1 and Rfv-2 '~'~z and the independent locus Rfv-3 '~ control the recovery of certain strains of rniee from Friend virus-induced erythroleukemia. The resistance conferred by these three genes correlates with the persistence of viremia after the initial development of erythroleukemia. It has been suggested that persistent viremia stimulates the production of neutralizing antiviral antibodies which bring about the eventual regression of disease in resistant animals. *~ In a similar example of interaction between independent genes, three haplotypes of the H-2 locus itself have been found to mitigate the restriction of SFFV replication by the Fv-2 resistance allele. TM Other host resistance genes which interact with the Fv-I locus have been identified. ~9 Host restriction of Ab-MuLV replication has been attributed to two loci, Av-I and A v.2, in the murine genome, s~ These genes confer susceptibility to Abelson virusinduced disease in an autosomal dominant manner analogous to the control of Friend virus replication and susceptibility to Friend virus disease expressed by the Fv-2 locus. Genetic susceptibility to Ab-MuLV replication and cell transformation in vitro and to Ab-MuLV-induced hematopoietic neoplasia in vivo is limited to, IIALB/c mice and a few closely related inbred strains. ~2' Av-i- and Av-2.mediated resistance to Ab-MuLV may be modulated by the H-'2 locus. ~27

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C. Stages in the Development of Murine Viral Leukemias 1. Leukemias Induced by the Friend Virus Complex Both the ai~emic and polycythemic forms of Friend erythroleukemia evolve through discrete stages which can be distinguished on the basis of the growth characteristics of the leukemic cells in vivo and in vitro. Increased proliferation of erythroid colonyforming progenitors in semisolid cultures of splenic tissue or bone marrow can be detected within several days after infection of susceptible mice with '~Friend virus. '6a,271.j~a.J76.aT~.s46.~J3The increased erythroid activity exhibited by cultures of hematopoietic cells established from mice with the anemic form of the disease is dependent upon the presence of endogenous or exogenous erythropoietin. In contrast, erytb.roid progenitor proliferation in cultures from animals with polycythemic disease does not require erythropoietin. Two to four weeks after inoculation with FV-P, marked increases in the numbers of spleen colony-forming cells in the peripheral blood and spleen of an infected mouse can be demonstrated by transfusing its blood or transI)larxting its spleen irtto a previously irradiated but uninfected recipient animal, '2s The early virus-induced enhancement of the proliferation of erythroid precursors and spleen colony-forming cells is attributable to the SFFV component present in the~viral inoculum. The SFFV component of the Friend virus complex also determines whether an anemic or polycythemic picture develops. The early manifestations of Friend erythroleuk~mia are believed to reflect the rapid infection of multiple target tissues (spleen, bone marrow, liver) by SFFV. However, permanent transformed ceil lines can not be produced by transplanting or culturing infected tissues within the first 2 to 3 weeks after inoculation. Thus, the leukemic cells present in the early stage of Friend erythroleukemia are best described as partially differentiated erythroid precursors which are not capable of dividing indefinitely in vivo or in vitro. In contrast, the later stage of Friend virus disease is characterized by the appearance within multiple tissues ef a uniform population of undifferentiated erythroblasts which proliferate indefinitely. ~l''zz''n The clonal origin of this cell population has been established by studies of their colony-forming properties in methyleeilulose culture aT~'~' and in irradiated mice. -~~ Many permanent erythroleukemia ceil-lines have been derived from mice with late-stage disease induced by FV-A or FV-P. Like the primary leukemias from which they are derived, these cell lines display variability with respect to erythropoietin sensitivity, globin gene expression, karyotypic abnormalities, capacity for subculture in methylcellulose, and tumorigenicity in syngeneic mice. a''Ta7 A large number of physical and chemical agents can induce these cells to undergo erythroid differentiation in vitro~ An intermediate stage in the evolution of Friend virus disease has been identified in which cells are undifferentiated, highly proliferative, and tumorigenic, but have not yet acquired the capacity for induced erythroid differentiation? ~1 Studies of the patterns of response of different routine erythroleukemia cell lines to the various differentiating agents have provided insight into the mechanisms of murine erythroid differentiation, a92's'' Cultures of normal routine bone marrow have been experimentally infected with various strains of Friend virus in an effort to reconstruct the pathogenetic events of Friend virus disease in vitro. Infection of normal murine hematopoietic cells with either FV-A or FV-P in semisolid culture results in the rapid proliferation of mature erythroid progenitor cells, ss.2''~.=''.zz3 These cells are neither clonogenic in secondary culture nor tumorigenic upon inoculation into syngeneic mice. Successful rescue of infectious SFFV from nonproducer ceils by coinfection with various replication-competent helper viruses has provided further evidence that the SFFV g~norne is the viral component required for the induction of erythroid progenitor proliferation early after infection. T M Early proliferation of erythroid pr~ursors after infection with FV-P also occurs in long-term cultures of normal murine bone marrow. ~~ Initially, erythropoietin is not

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required to stimulate erythroid proliferation in these cultures. However, viral stimulation of erythropoiesis is not sustained, and most cultures die out 8 to 12 weeks after infection. Sustained crythropoiesis may be induced by the addition of serum from anemic mice to the culture medium. Under ~bese conditions, the self-~imited stimulation of erythroid progenitor cells is followed by a period of proliferation of immature erythroid precursors which may continue for more than 40 weeks. These cells contain little or no llemoglobin, are clonogenic in semisolid culture media, and form spleen colonies in irradiated syngerteic mice. However, they retain their dependence on the presence of an adherent cell layer for continued growth and do not give rise to permanent lines of transformed cells. Additional passage on an adherent ceil layer derived from normal routine bone marrow is required for the eventual establishment of permanent Friend cell lines in the long-term culture system. Thus, according to criteria of cellular proliferation, differentiation, and tumorigenicity, the early and late stages of.Friend virus disease observed in in vitro systems correspond closely to the stages defined by studies of cultures established from infected mice.

2. Leukemias Induced by Replication.Competent Friend Murine Leukemia Virus The presence of two viral components in all Friend virus stocks imposes a~ additional level of complexity on the analysis of the patho~enesis of Friend virus disease. This problem can only be resolved by experimental a~proaches which examine the pathogenetic properties of the individual viruses. To a large extent, this has been accomplished by investigations of the replication-competent component of theFriend virus complex: F-MuLV. Studies of the growth characteristics of leukemic ceils from animals infected with purified F-MuLV have added to our understanding of the stages of Friend virus disease. In these experiments, the helper virus was purified free of FSFFV either by end-point dilution cloning in murine fibroblast culture 3"'~ or by molecular cloning of infectious vital DNA? ~' Newborn mice of susceptible strains ordinarily die of erythroleukemia 6 to 14 weeks after inoculation with F-MuLV. Despite the extreme aggressiveness of this disease, attempts to establish permanent cell lines from the spleen or bone marrow of diseased animals have been unsuccessful. However, if transfusions of packed red blood ceils are given to leukemic mice starting 6 weeks after infectioti, .their survival can be extended by approximately 8 weeks. '62 Leukemic cells isolated from transfused mice exhibit a more transformed phenotype than leukemic cells obtained from untransfused animals. Approximately I in l0 Gcells can be propagated indefinitely in vitro or by transplantation into syngeneic mice, ~6zThe transplantability of the leukemic cells forms the basis of the staging system for F-MuLV~ induced disease. The leukemic tissues in stage I and stage II disease are histologically identical, but transplantation is possible only in stage II. Stage I disease may thus be characterized as a rapid, polyclonal hyperplasia of erythroid progenitor ceils induced by infection with F-MuLV. 4~ Several pathologic differences have been identified between the erythroleukemia resuiting from serial passage of stage II cells in syngeneic mice and that induced b)r primary inoculation with F-MuLV. The transplantable erythroleukemia exhibits more rapid disease progression, more extensive bone marrow involvement, and milder anemia. *~z garyotype analysis of transplant recipients indicates that the leukemic ceils are o f donor origin,. The transplantable leukemic cells do not contain SFFV but do express MCF virus envelope glyeoprotein antigens. ~s2 These MCF viruses presumably arise early in the disease by recombination between F-MuLV and x~notfopic endogenous viral sequences in the mouse genome. Their presence in transplantable leukemic cells suggests that MCF viruses play a significant role in the pathogenesis of stage 11 disease. 6~s

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Additional biological differences exist between the leukemic cells in stages I and II. Ordinarily, stage I leukemic cells and bone marrow cells from normal, uninfected mice survive for only 24 to ,*8 hr in suspension culture, while stage II cells divide indefinitely and form permanent erythroleukemia cell lines. "6~ However, growth in the presence of conditioned medium from the WEHI-3 cell line'~ results in the immortalization of 100% of leukemic tissue e):f]ants from mice with stage i disease. WEHI-3 is a murine myelornonocytic leukemia celi line which produces the multilineage hematopoietir growth factor interleukin 3. ~'~" The use of this conditioned medium permits only short-term (3 to 5 weeks) propagation of hematopoietic cells from normal routine bone marrow. ~ The siage l-derived cell lines produced under these conditions are dependent upon the presence of conditioned medium or purified intefleukin 3 for their growth in vitro. Although immortal, these calls are unable to engraft in syngeneic mice. Microscopic examination indicates that the immortalized cells are of myeloid rather than erythroid origin. This cell population consists of 95 to 99% peroxidase-positive mye[oblas~s and ! to 5~0 more rna:ure myr elements.-6~ The doubling time i~ 18 to 24 hr under optimum culture conditions, '~~ compared to !8 to 20 hr for the proerythroblast cell lines which can be established from stage II leukemic tissues. '6~ Like stage II cells, ~tage I-derived ceil lines express MCF virus envelope antigens. 4~~This observation suggests that the recombination event which generates MCF viruses occurs early in the course of F-MuLV-induced disease. Enhanced expression of the v-Ki-ras oncogene by stage I-derived ceil tines can be detected by blot hybridization gel analysis of cellular messenger RNA. .6~ The evolution of malignant myeloblastic transformation induced by F-MuLV has also been-investigated in a completely in vitro system. ;~'zsa Serial assessments of myelomonocytic differentiation, growth factor requirements, and in vivo tumorigenicity' were performed after infection of long-term routine bone marrow cultures with FMuLu Three stages of in vitro leukemog9 were identified by these criteria. In the first stage, increasing responsiveness to granulocyte-macrophage colony-stimulating factor (GM-CSF) permits the subculturing of primary cultures 12 to 24 weeks after infection. Both primary and secondary cultures are dependent upon the presence of an adherent cell layer. The first stage of in vitro leukemogenesis is also characterized by an increasing proportion of immature gran~tocyte precursors in the celt population. The unusual degree of responsiveness to GM-CSF exhibited by cells in this stage is limited to stimulation of proliferation, while differentiation appears to be blocked. The second stage of leukemogenesis consists of the development of growth-factor independence. The cells, now almost exclusively mydoblasts, no longer require an adherent layer and can proliferate in pure suspension culture. Progression to this second stage occurs an average of 36 weeks after infection of the primary cultures. Between 50 and 70 weeks after infection, ceils obtained from these cultures exhibit tumorigenicity in irradiated syngeneic mice. The identification of discrete stages of murine viral leukemogenesis in vivo and in vitro suggests that the expression of a fully malignant leukemic phcnotype involves the sequential activation of a number of cellular genes. These genes are also likely to function in normal hematopoiesis. Activation of these genes during malignant hematopoiesis appears to involve the loss of regulatory mechanisms governing their normal expression and the responsiveness of hematopoietic cells to their products. Multistcp activation of cooperating cellular oncogenes has been dem~onstrated in other expc.rimental systems,"','~ and is implicated in the pathogenesis of certain human maligrianties. 'j~ Future studies in this field will doubtless focus on the relative patterns of enhanced oncogene expression in the different stages of leukemia, and.their relationship to the loss of growth-factor dependence which characterize.~ .'.het~nsition from early to late stages of disease.

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D. Insertional Mutagenesis and the Promoter Insertion Hypothesis In 1981, Hayward et a13 s'-'36 reported that virally induced avian lymphoid malignancies synthesize high levels of messenger RNA consisting of virus-specific sequences covalently linked to cellular sequences. Blot hybridization get analysis h~dicated that the cell-derived sequences are homologous to the cellular oncogene c-myc? s~ These investigators concluded that the chance integration of proviral DNA "upstream" and adjacent to the c-myc oncogene results in the stimulation of c-myc expression. Under these conditions, the integrated proviral DNA sequences act as a promoter for the transcription of the c-myc oncogene. Since the Us region of the provira! LTR is known to encode a promoter for virus-specific transcription, the authors reasoned that the LTR is the critical portion of the provirus which must be integrated adjacent to an oncogene in order to promote its expression. Further investigation demonstrated that the promoter need p.,at be positioned upstream from the c.myc oncogene, nor is the transcriptional orientation of the integrated provirus required to be the same as that of c-myc? s2 These findings suggest that a c/s-acting transcription-enhancing function is subserved by the integrated proviral sequences. The presence of enhancer sequences for virus-specific transcription within the U, region of the LTR also implicates this region in the enhancement of oncogene transcription. The insertion of a single LTR in proximity to the oneogene appears to be the only requirement for viral activation of cellular oncogene transcription. The activation of cellular oneogertes by promoter insertion has beer~ shown to be an important mechanism of carcinogenesis for several classes of retloviruses whose genpines do not contain oncogenes. Further studies in the avian bursal lymph0ma system have indicated that promoter insertion brings about several types of mutations which affect oncogene expression. T M These include: (1) insertion of the provirus itself, (2) partial deletions within the gag, pol, and/or env genes that prevent further virus replication, and (3) base-substitution point mutations within the cdlular coding region for c-myc. Insertional mutagenesis also appears to play a role in mammary carcinogenesis induced by the mouse mammary tunlor virus (MMTV), a replication-competent B-type retrovirus. Two common loci (int..l and int-2) for MMTV provirus integration have been mapped within the murine genome. "~j''a' Proviral insertion adjacent to these loci results in low levels of transcription of cellular sequences which are adiacent to the inserted provirus; transcription proceeds in a direction away from the int-I or int-2 locus, with respect to the position of the integrated proviral sequences, '~'(A~ The int-I and int.2 loci lack sequence homology to the known oncogenes, 48s'.93 indicating that they constitute a new class of growth-regulatory genes. Complete nucleotide sequence analysis of the int-1 locus has recently been reported, allowing the tentative identification of a proteirt-eoding domain within the gerte.6~ The proviral integration sites are invariably found to be outside the putative protein-coding region, 69~ as would be predicted by the promoter insertion hypothesis. The role of insertional rnutagenesis in the pathogenesis of murine viral leukemias has also been investigated. Two common regions for proviral insertion (RMoint-I and M L VI.I) have been identified within the cellular chromosome complement of some Mo.MuLV-induced rat thymic lyrapl~omas:"s'~ An additional site for the integration of MCF proviruses (Pinvi) has been detected in a number of routine thyraic malignancies. '0~ Restriction mapping of cellular DNA sequences adjacent to integrated provirases has demonstrated that in some murinr thymie malignancies, the integration site is adjacent to the e-myc locus on chromosome 15, '00'6~' with resulting increased transcription of the c- my'r oncogene. '~~ The importance of e-myc activation in the promoter insertion model of viral carcinogenesis has been demonstrated for avian bursal tumors 2ss,'')'',~ and routine thymic malignancies.~..~176 However, the mechanism of e-myo-mediated cell transformation re-

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mains unclear. Additional studies arc needed to elucidate the function of the c-myc oncogene in the control of normal and malignant cell proliferation. Interestingly, insertiorml activation of a second cellular oncogene of the same broad functional class, r has been demonstrated in several marine plasmacytoid lympho~'ar~omas. "9" The provirus responsible for c-myb activation is derived from a defective strain of MoMuLV. Further analysis of the molecular and pathogenetic events in this cell-virus system may prove useful in clarifying the universaiity and pathogenetic significance of the insertional mutagenesis model. VI. VIRAL G E N E T I C D E T E R M I N A N T S OF L E U K E M O G E N I C 1 T Y Recombinant DNA techniques and related biochemical methods have provided in. sight into the molecular basis of the host and cellular determinants of susceptibility to leukemia. These sol~histicated approaches have also been applied to the analysis of the MuLV genome and have helped to elucidate the roles ~layed by various !eukemoge~ic routine retroviruses (i.e., replication.competent helper viruses, endogenous viruses, SFFVs, and MCF viruses) in the pathogenesis of the marine leukemias. While none of these viruses contains an oncogene, recombinant DNA methods have permitted the identification of specific sequences within the MuLV genome which contribute to leukemogenesis, interestingly, not one but severaI regions of the viral genome participate in leukemogenesis. A. Viral Genes Encoding Host-Range Specificity Other than insertional mutagenesis, no aspect of murine viral leukemogenesis demonstrates the importance of direct interaction between viral and cellular genetic information more clearly than the determination of viral host range. The MuLV gene product which is responsible for binding to specific cell-surface receptors at the beginning of the viral replicative cycle is gpT0"~-. The existence of specific receptors on the surface of marine cells for gp70 was first recognized by DeLarco and Todaro. TM These investigators developed a quantitative binding assay for the interaction between purified, radioiodinated gpT0 and its specific cell-surface receptor. They demonstrated that binding is inhibited by antisera directed against the purified #ycoprotr or by prr fection of the cells with viruses containing envelope glycoproteins which are antigenically related to the purified glycoprotein used in the assay. The degree of competition for receptor binding observed in the assay reflects the antigenic, relationship between the competing glycoproteins. Thus, preinfection with various ecotropic MuLVs markedly inhibits the recept6-~ binding of radioiodinated gp70 molecules purified from Rauscher MuLV, while tlo ~inhibitory effect is ex,rted by the preinfection of cells with amphotropie or certain xenotropic MuLVs. A number of :tudies have attempted to relate variations in the fine structure of the env gene with the expression of the various host-range phenotypes. Genetic alterations in MuLV host range arise by recombination events which have been mapped to the env geneSO.B3.t4t.t41.t$O~163.t6S.l~6.|Sl,ttll,227.~t69,437.44~.t~35.$99.67~The env gene encodes the pattern of glycosylation as well as the primary structure of the envelope pol~peptides. Both are important biochemical determinants of host-range Specificity. t4t'~tt'a'a's'3's" Sequencing of the envgene of the cloned DNA genomes of three Friend MCF viruses (Fr-MCFVs), *20 Moloney MCF virus, sa MCF 247 virus, 2s9.3'~and two NZB xenotropic MuLVs, 4s'.s's and comparison with sequence data from various ecotropic MuLVs demonstrated extensive homology among all viruses examined in the portions of the gene encoding plS{E) and the carboxy-terminal half of $p70. The amino-terminal half of the gpTO-coding domain is also similar among thz.sr MCF viruses and xenotropic vi. ruses but differs considerably from the corresponding region of the env gene of the

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ecotropic MuLV strains. ~2.3'~'32~176 The sequence data suggest that this "differ-uncial region" is of endogenous origin. Since this region is structurally very similar in MCF viruses associated with erythroleukemia and tylnphoid leukemia, Koch et aL ~~ concluded that it encodes deternfinants of xenotropic and polytropic host range. Other attempts to elucidate the molecular genetics of viral host-range specificiW have focused on the gag gene of the ecotropic MuLVs. The portion of the gag gene that encodes the internal virion protein p30 has been shown by oligonucleotide mapping ~',''~.~3s and by comparisons of the electrophoretic mobility ~"2'~t~ and tryptic peptides ~~ of the p3O proteins of various ecotropic MuLV strains to be responsible for determining viral N- and B-tropism. Recently, DesGroseillers and Jolicoeur ~s applied molecular cloning techniques to more precise characterization of the region of the MuLV genome which encodes N- and B-tropism. These investigators constructed hybrid viral DNA genomes consisting of portions of the cloned DNA of N-tropic and B-tropic endogenous MuLVs isolated from BALB/e mice. Microin~ection of the hybrid DNA genomes into Fv-I- Sc*I murine cells resulted in the recovery of infectious recombinant viruses which were then tested for N- and B-tropism in routine fibroblast cultures. By restriction enzyme mapping and nucleotide sequence analysis of the DNA genomes of several recombinant viruses, the sequences encoding N- and B-tropism were assigned to a 502-base pair fragment in the p30~coding region of the sag gene. A difference in only two amino acid residues was found between the p30-coding sequences of N-tropic and B-~ropic BALB/c MuLV$, indicating that the N- or B-tropism of these viruses is specified by these residues. B. Viral Genes Encoding Leukemogenicity The analysis of recombinant viruses to identify the leukemogenic regions of the retrovirus genome was first applied to the avian retroviruses. TM In this study, spontaneously occurring rer of oncogenic and nononcogenic avian retroviruses were tested for their ability to induce hematologic malignancies and solid tumors in chickens. The incidence of the various neoplasms and their latent periods after inoculation were determined as indices of the relative pathogenicity of the recombinant viruses and their parental virus strains. The genome structure of each recombinant was analyzed by comparing its oligonucleotide composition and the electrophoretic mobility of its structural proteins with those of the parental strains. The observed correlations between the presence of specific sequences derived from the leukemogenic parental virus and the pathogenicity of the recombinant virus allowed the first precise identification of the transforming sequences in the genome of a retrovirus which did not contain an oncogene. Using this technique, Robinson et al. '~' isolated a leukemogenie avian retrovirus (NTRE-7) wtIieh arose by recomi0ination between a nondefective strain (Prague-B) of avian sarcoma virus and a nonpathogenic endogenous avian retrovirus (Rous-associated virus-0 or RAV-O). Comparative analyses of genome structure revealed that only the U3 region of NTRE-7 is derived from. the acutely transforming parent. The remainder of the NTRE.7 genome is identical to that of RAV-0. The authors concluded that NTRE-7 was generated by a single recombination event in the U~ region, and that this region confers ieukemogenicity on the recombinant virus. However, other avian retroviruses (the RAV-60 family) generated by recombination between acutely transforming avian sarcoma viruses and nonpathogenic endogenous avian viruses, were found to induce a higher incidence of short-latency malignancies than NTRE-7. Since the U, region of the RAV-60s is similar to that of blTRE-7 in oligonucleotide structure, at least one other portion of the RAY-60 genome must be responsible for their greater pathogenicity. The oncogenic potdntial of the avian leukosis viruses therefore appears to be determined by at least two regions of the viral gun?me.

Volume 5, Issue 3 AMPHO

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FIGURE 3. Schematicrepresentation of the rnolr cloningof the L-9 recombinant vir~tl gcnomr Abbreviations: C, Cia/; H, Hindl[l; K, Kpnl; R, EcoRI' and S, $phl. The leukemogenic regions of the MuLV genome have been investigated in similar experiments. However, the recombinant viral genomes explored in these studies are constructed entirely in vitro using recombinant DNA techniques. Restriction endonucleases are used to excise a predetermined region of the cloned DNA genome of one MuLV strain. The excised sequences are then substituted for the corresponding region of the cloned DNA genome of another strain using the same restriction enzymes as well as DNA ligases (Figure 3). There is virtually no limit to the number of hybrid viral genomes which can be engineered between two parental viruses using this technique. Infectious recombinant viruses are produced by transfection of these hybrid DNA constructs into cultured mouse fibroblasts. The recombinant viruses generated in this manner are inoculated into mice to analyze the incidence and latent period for the emerg~ enc e of leukemia and the host-range specificity of these viruses. Characterization of the genome structure of the recombinants is generally performed by restriction mapping rather than by comparison of oligonucleotide digests. I. The env Getze The first application of molecular cloning techniques to the study of the determinants of leukemogenicity within the MuLV genome was reported by Oliff et al. in 1980. 457 These investigators identified an 8.5 kbase pair molecule of F-MuLV DNA which yielded infectious, leukemogenic F-MuLV upon transfection into NIH 3T3 routine fibroblasts. From this cloned full-length DNA genome, a 4. i kbase pair restriction fragment was subcloned. This fragment consisted of 3.0 kbase pair~ derived from the 3' terminus of the genome, 0.6 kbase pairs representing the 3'- and 5'-terminal redundant sequences, and 0.5 kbase pairs from the 5' terminus of the genome. ~" When NIH 3T3 fibroblasts were transfected with this fragment of the F-MuLV DNA genome and then infected with a nonpathogenic amphotropir strain of MuLV (4070-A), leukemogenie viruses were recovered, The recombinant nature of these pathogenic viruses was demonstrated by radioimmunoprecipitation assays showing that their envelope glycoproteins are antigenically related to that of F-MuLV, while their 65,000-dalton eaffpolypeptide precursors are derived from 4070-A. Individual recombinant viruses generated in this experiment were able to induce erythroleukemia in approximately 50~

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IN VITRO GENERATEDRECOMBINANTMaLV DNA LTfl

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ENV LTR Leukemia I.atm~ gpTO ptSE Incidu~ OVNI~)

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.

.

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~/////////~,

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FIGURE 4, Schematic representation of all recombinant viral genornes generated between amphotropie M~LV 40"10, F-MttLV, and Fr-MCF, b=nkemogenlcity data refers to both overt and microscopic disease. Latency refers to the maximum time unti! disease, Many animals develop leukemia before the maximum latent period.

of Swiss mice within 6 to 8 weeks after neonatal inoculation. The investigators concluded that the leukemogenic potential of F-MuLV was encoded by the 4. I kbase pair DNA fragment containing env- and gag-specific sequences as well as the LTR. '5~ In a more recent study, Oliff and RuscettP" used a smaller subgenomic fragment of cloned F-MuLV DNA to define more precisely the contribution of the F-MuLV env gene to leukemogenicity. They isolated a 2.4 kbase pair DNA fragment containing approximately 0.7 kbase pairs from the 3' end of the po/gene and 1,7 kbase pairs from the adjoining 5' end of the envgene. The eavgene sequences encoded gp70 and the Nterminal four fifths of p 15(E). Ligation of this DNA fragment to a molecularly cloned fragment of viral DNA from a nonpathogenic amphotropic MuLV (clone 4070) yielded an 8.3 kbase pair hybrid DNA, molecule. Transfcction of this hybrid DNA into NIH 3T3 fibroblasts produced a replication-competent ecotropic recombinant MuLV. This recombinant virus (Sa25-H) induced erythroleukemia in approximately 25% of NIH Swiss mice within 6 months after neonatal inoculation (Figure 4). The erythroleukemia

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induced by thi~ virus was identical to that caused by F-MuLV in gross and microscopic pathology. However, F - M u L V induces a higher incidence of leukemia (100%) and exhibits a shorter latency (6 to 8 weeks) than 5a25-H virus,Thus, while some determinants of the Icukemogcnicity of F - M u L V map to the 2.4 kbase pair D N A fragment encompassing the pol-env junction and most of the any gone, additional sequences arc required for expression of the full leukcmogenic potential of F-MuLV. Radioimmunoprecipitation assays demonstrated that an 80,000-dalton precursor to gp70 is present in NIH 3T3 fibroblasts infected with 5a25-H. This precursor is antigenically unrelated to the envelope $1ycoprotein gpT0 of the MCF viruses. However, an 80,000-daI.ton glycoproteit~ which cross-reacts with the envelope glycoprotein of Moloney MCF virus is expressed in NIH 3T3 cells infected with spleen homogenates from leukemic mice which had been inoculated with 5a2S-H. The ability of 5a25-H to induce MCF virus formation may be involved in [eukemogenesis. The specific r to leukemogenes~s made by the recombinant cnv gone of the SFFVs present in stocks of Friend virus or Rauscher virus ~.as been investigated using the molecularly cloned DNA genome of the Lilly-Steevcs strain of SFFVp. ~'3~p Infectious SFFV was recovered from NIH 3T3 murine fibroblasts transfectcd with cloned SFFV DNA following superinfection with a replication-competent helper virus (F-MuLV or Mo-MuLV) or cotransfection with molecularly cloned DNA from the helper virus. Trausfection experiments using subcloned fragments of the SFFV DNA genomc indicated that only a 2.0 kbase pair DNA fragment is required for the recovery of viruses with spleen focus.forming activity and erythroproliferative activity in susceptible mice. The envelope glycoprotein gp52 of SFFV was invariably detected in cultures which produced biologically active SFFV. This glycoprotein was also found in the spleens of leukemic mice infected with SFFV produced in transfected cells. Thus, it appears likely that the SFFV env gcrte encodes determinants of both spleen focusforming activity and ieukemogenicity. This hypothesis was confirmed by the observat[ort that site-directed mutagenesis of the envgene in cloned SFFV DNA abolishes both the spleen focus-forming activity and the leukemogenic potential of viruses recovered from fibrobIasts transfected with these DNAs. 36' The appearance of polytropic, Ieukemogenic MCF viruses in many murine viral hernatopoietic malignancies provided tl~e first indicat[ort of the important role played by the MuLV any gone in determining leukemogenicity. MCF viruses arise by recombination between ecotropic and either xenotropic or polytropic parental viral gr within the gpTO-coding region of the any gene. This recombination event confers on the MCF viruses not only their poiytropic host range, but also their unique lcukcmogenie properties. Many MCF viruses are more leukemogenic than their ecotropic parent in the same strains of mice as ,sellas in heterologous species. Other MCF viruses are less leukernogenic than their ecotropic parent. The different degrees of leukemogenicity occur despite the fact that these viruses exhibit the same host range and have undergone sitnilar recombination events within the cnv gone. ~'''L''7,'s''2~'~'~'4s~ Unique but genetically similar MCF viruses have been isolated from thymic, splenic, and bone marrow tissue of leukemic AKR mice. However, MCF viruses were present only in the thymuses of preleukemic mice from the same strain. "~s The heritable resistonce to thymic malignancies exhibited by the NZB strain of mice is genetically linked to their ability to suppress the generation of recombinant viruses. Reciprocal allogeneic ~grafting of thyrnir tissue and bone marrow between AKR and NZB mice demonstrated that these genetic effects are mediated by the epithelial or stromal tissue of the thymus, and not by thymic |ymphocytes or bone marrow-derived hematopoietir cells, tQ*Wholegenome oligonucleotide mapping x~ and nucleotide sequence analysis of the gpT0coding region of the any gone2~9 have been used to compare the structures of the genomes of the nonleukemogenic ecotropic endogenous virus Akv and various leukemo-

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genie MCF viruses. The MCF viruses used in these studies were generated by recombination between Akv and one or more as yet uncharaeterized xenotropic endogenous viruses during leukemogenesis in AKR or (AKR • NZB)F~ hybrid mice. The 5' portion of the gp70-coding domain and the 3' portion of the plS(E)-coding domain of the env gene are two of at least three distinct regions in which the genomes of the MCF viruses differ from those of ti~cir ecotropic parent, The presence of sequences which are not derived from Akv in the MCF virus genome correlates with ieukcmogenicity. Significantly, the extreme 5' and 3' portions of the env gene are often found to express nonAkv sequences independently.~~ This finding suggests that some of the recombination events within the env gene which generate MCF viruses take place 3' to the gp70coding domain. Therefore, some of the resulting recombinant viruses would be expected to exhibit an ecotropic rather titian polytropic host range because their envelope glycoproteins are derived entirely from their ecntropic parent. The isolation of such recombinants from the thymuses of mice of the leukemia-prone HRS/J strain has been reported. 227,~G, Comparative oligonucleotide mapping of viral RNA and restriction mapping of molecularly cloned viral DNA have identified differences in genome structure among different MCF virus strains as well as between MCF viruses and their ecotropic parental strains. One region of the MCF virus genome which exhibits sequence variability is the plS(E)-coding domain of the cue gene.3'~ In general, the pl 5(E)-coding region is of recombinant origin in MCF viruses associated with thymie malignancies. The sequences at the 5' end and in the center of this region are derived from the r parent (Akv) of MCF 247 virus and related leukemogenic MCF viruses. The 3' portion of the plS(E)-coding domain and the adjacent U~ region of the 3"-terminal redundant sequences originate from the nonecotropic parent. In contrast, the entire plS(E)-eoding domain of the env gene of nunleukemogeuic MCF viruses is derived from the nonecotropic parental virus. These findings provide further evidence that determinants of leukemogenicity reside in the plS(E)-eoding region of the MCF virus env gene and that a recombination event in this region is required for the expression of its leukemogenie potential. Interestingly, oligonucleotide mapping fails to demonstrate significant differences between leukemogenic and nonleukemogenic MCF viruses in the structure of the gp70-coding domain, 3,s despite the observed recombinant origin of the extreme 5' end of the env gene in several Akv-derived leukemogenic MCF viruses.~~ A different approach has been applied to the analysis of the Fr-MCFV genome. Restriction mapping of cloned Fr-MCFV viral DNA demonstrates a 1.0 kbase pair region within the envgene which differs from the corresponding region of the F-MuLV genome. 4s~ A probe made from a 0.4 kbase pair DNA fragment subcloned from this region and designated pLEK was found to hybridize with cloned Fr-MCFV DNA, but did not hybridize to cloned DNA from either F-MuLV or amphotropic MuLV. This probe also detected two size classes of mRNA homologous to the env gene of FrMCFV within the hematopoietic tissues of normal NIH Swiss mice, uninfected T lymphocytes from a chemically induced thymic leukemia, and Fr-MCFV-infected r roleukemia cells. RNA homologous to the pLEK probe is expressed at 400-fold greater levels in infected erythroleukemia cells than in either normal hematopoietic tissue or cells cultured from a chemically induced thymie leukemia. The authors suggested that the transcriptionally active sequences within the envgene which hybridize to the pLEK probe may be involved in the recombination event which gives rise to Fr-MCFV. Inhibition of the replication or spread of MCF viruses has been shown to decrease the incidence of F-MuLV-induced erythroleukemia. Interference with MCF virus infection may occur as neonatal mice mature, is( Adult NIH Swiss~mice are normally resistant to F-MuLV-induced leukemia. These mice fail to generate Fr-MCFV following infection with F-MuLV. However, treatment of adult mice with X-irradiation,

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phenylhydrazine, or silica prior to inoculation with F-MuLV dramatically increases their susceptibility to MCF virus formation and vitally induced leukemia,ss4 In some strains of mice, inhibition of MCF virus infection correlates with the expression of a 70,000-dalton glycoprotcin which is antigenically related to the gp70'"v of the MCF viruses?~ This interference with viral infection can be reversed in vitro by treating cells before infection with 2-deoxyglucose or tunicamycin, which inhibit the glycosylation of retrovirus envelope glycoproteins.~~ Thus, there appear to be at least two mechanisms of interference with MCF virus infection: impa'rment of the host immune response to the envelope glycoproteins of the MCF viruses, and inhibition of the binding of the viral envelope giycoproteins to their specific cell-surface receptor. Analysis of retroviral interference groups has provided evidence for the existence of specific receptors for the recombinant MCF viruses which arise during pathogenic infections of mice with ecotropic strains of MuLV. sl3 Further studies of the immune response elicite0 by the recombinant envelope glycoproteins of the MCF viruses and their interaction with specific cell-surface receptors promise to provide greater understanding of the role of these viruses in routine leukemogenesis. Neurotropic ecotropic wild-mouse leukemia virus has been purified by microi~ection of molecularly cloned f~:ll-length viral DNA into cultured NIH 3T3 routine fibreblasts. 2~ The N-tropic ecotropic virus recovered from microinjected cells was capable of inducing hind-limb paraplegia after inoculation into susceptible mice. This study indicates that the genome of the ecotropie wild-mouse leukemia virus contains all of the information required for pathogenicity. DesGroseiliers et a1.'24 constructed hybrid DNA genomes with sequences derived from molecularly cloned DNA of both paralysis-inducing ecotropic wild-mouse leukemia virus and nonpathogenic amphotropic MuLV 4070-A. The infectious recombinant viruses recovered after microinjection of the DNA hybrids into NIH 3T3 cells were tested for their ability to induce neural disease upon inoculation into newborn SIM.S and SWR/J mice. Several recombinant viruses with varying degrees of neurotropism and pathogenity were identified. Restriction mapping of the recombinant DNA genomes assigned the paralytogenic determinants to a 3.9 kbase pair DNA fragment representing the 3' end of the pol gene and the entire env gene of the neurotropic MuLVs.'2~ MCF viruses have recently been isolated from the spleens of mice with virus-induced hind-limb paraplegia. However, these viruses have not been found within the central nervous system, nor do they produce neural disease after inoculation into uninfected newborn mice of susceptible strains. '~4 2. The Uj Region of the 3"-Terminal Redundant Sequence Several lines of evidence indicate that the principal viral genetic determinants of leukemogenicity reside in the U~ region of the 3'-terminal redundant sequences. The first demonstration of the importance of this nonprotein-coding region in the deterruination of the leukemogenic potential of MuLVs was provided by analyses of the terminal redundant sequences of the genomes of the Gross passage-A strain of MuLV and the nonleukemogenic ecotropic endogenous virus Akv. Transfection of NIH 3T3 murine fibroblasts with the molecularly cloned fall-length DNA genome of Gross passage-A MuLV yielded an infectious virus with ecotropic, N-tropic, and leukemogenic properties.'" Thus, the genome of ecotropic Gross passage-A MuLV contains sequences which contribute to leukemogenesis. However, polytropic recombinant viruses have been recovered from Gross passage-A MuLV-induced thymic leukemias,I'* indicating that MCF viruses may also play a role in their pathogenesis. Restriction mapping of the cloned DNA genome of Gross passage~A MnLV'" yielded results similar to those obtained for the Akv strain of MuLV 'on except at the 3' end of their genome~;. These restriction mapping data are in agreement with earli9 findings obtained by corn-

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parative oligonucleotide mapping of the RNA genomes of these MuLVs. 6~Nucleotide sequence analyses of the LTRs of the cloned DNA genomes of the Gross passage-A TM and Akv 6~' strains of MuLV re~tealed that the differences between these viruses are confined to the U~ region. The LTR sequence of Gross passage-A MuLV contains only one copy of the U~ tandem direct repeat present in the LTR of the Akv strain. The retained copy of the direct repeat is rearranged by the insertion of a 36-base pair sequence and by the presence of five point mutations. A sixth point mutation is present within the U~ region outside the tandem repeat sequences. These findings suggest that the leukemogenic potential of the Gross passage-A strain of MuLV is encoded by those sequences within the U, region of the 3'-terminal redundant portion of its genome which differ from the corresponding sequences in the genome of Akv. TM In an effort to validate this hypothesis, DesGroseillers et al. '2~ cloned a subgenomic fragment of Gross passage-A MuLV DNA consisting of part of the gp-70 coding domain and all of the p lS(E)-coding domain of the env gone, plus the LTR. This DNA fragment was substitute:lfor the corresponding region of the D N A genome of a weakly leukemogenic B-tropic ecotropic endogenous virus isolated from BALB/c mice (BALB/c MuLV). The resulting hybrid D N A was microinjected into SC-I murine cells.The ecotropic recombinant virus recovered after microinjectionwas B-tropic, reflectingthe contribution of the gag gene of the B-tropic parental virus. However, this virus was highly leukemogcnic because of the presence of sequences derived from the 3' end of the genome of the parental Gross passage-A M u L V strain.In subsequent experiments designed to evaluate the relativeinfluence of the ear gone and the U3 region in determining leukcmogenicity, a nonleukemogenic N-tropic strain of BALB/c M u L V was sometimes substituted for the weakly leukemogenic B.tropic strain.T M In either case, when the contribution of the highly leukemogenic Oross passage-A parental virus was limited to the U~ region, the resulting recombinant viruses demonstrated intermediate leukemogenic potential. Addition of the plS(E)~coding region of the Gross passage-A MuLV env gone enhanced the leukemogenicity of the recombinant viruses, while the further addition of approximately 1.0 kbase pairs from the 3' end of the gpT0-coding domain conferred on the recombinants the full leukemogenic potential of the Gross passage-A parental strain. In contrast, recombinant viruses which derive only env gone sequences from Gross passage~A MuLV were no more |eukemogenic than their BALB/ c MuLV parent. These findings indicate that the U~ region of the :;'-terminal redundant sequence can impart some leukemogenic potential to ecotropic MuLVs, but additional determinants encoded within the envgene are required for maximum leukemogenicity. Independent confirmation of the role played by the terminal redundant sequences of the MuLV genome in the pathogenesis of leukemia was provided by analyses of the genomes of recombinant viruses constructed from the molecularly cloned DNA of the SL3-3 and Akv MuLVs. SL3-3 is a leukemogenic ecotropic MuLV, while the ecotropic endogenous Akv strain is nonpathogenic. Assays of the leukcmogenicity of the recombinant viruses and restriction mapping of their DNA genomes indicated that the leukemogenic potential of SL3-3 was encoded within a 3.8 kbase pair fragment of the SL3-3 genome which contained the LTR sequences, the gag gone, and the if' 30% of the pol gene. ~s~ Interestingly, reciprocal recombinants in which these sequences were derived from Akv while the remainder of the pol gone and the entire env gone were derived from SL3-3 were not pathogenic. 3~~The subsequent construction of a leukemogenic recombinant whose DNA genome derived onIy its LTR from SL3-3, and all of its coding sequences from Akv, localized the primary leukemogenic determinant of SL3-3 to the terminal redundant sequences24~ Comparative nur sequence analyses of the LTRs of the DNA genomes of SL3-3 and Akv demonstrated structural differences only within the U~ region. TM The role of organotropism in the pathogenesis of murine viral leukemias is complex.

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Various p~thogenic MuLV strains differ in their predilection to'cause erythroleukemia, myeloid leukemias, T- and B-lymphocyte neoplasms, and neurologic disease. The molecular basis of organ,tropism and its relationship to leukemogenicity can also be analyzed by recombinant DNA techniques. DesGroseillers et ai. 12a constructed hybrid DNA gun,rues by in vitro recombination between the cloned full-length DNA gun,rues of nonthymotropic N-tropic BALB/c MuLV and either thymotropic B-tropic BALB/ c MuLV or Gross passage-A MuLV. The recombinant viruses generated from these DNA hydrids were inoculated into newborn mice. After 20 to 30 days, the thymuses were explanted into suspension culture and assayed for the presence of infectious ~,irus. Recombinant viruses whose gun,rues contained terminal redundant sequences derived from either of the thymotropic parental strains (B-tropic BALB/c MuLV or Gross passage-A MuLV) were capable of replicating in thymic tissue. No other region of the gun,me appears to be required for the expression of thymotropism. The investigators performed comparative restriction mapping and nur sequence analysis of the LTR regions of the DNA gun,rues of the parental viruses. All structural, differences between the LTR sequences of the thymotropic and nonthymotropic parental viruses were found within the U3 region. A subsequent study from the same laboratory provided further insight into the relationship between the viral genetic determinants.of leukemogenicity and those of organ,tropism by analyzing hybrid DNA genomes constructed from DNA clones of Mo-MuLV and amphotropic MuLV 4070-A. ~2' These parental viruses reliably induce thymic and nonthymic leukemias, respectively. The infectious recombinant viruses recovered after transfection of the hybrid DNA gunpines into NIH 3T3 cells were assayed for leukemogenieity in newborn HIH Swiss mice. Restriction mapping of the DNA gun,rues of the recombinant viruses demonstrated that the principal determinant of the ieukemogenicity of Mo-MuLV or amphotropic MuLV resides on a 1.5 kbase pair DNA fragment containing the viral LTR sequences. Recombinant viruses whose genomes contained LTR sequences derived from Mo-MuLV were found to induce thymic malignancies, while recombinants with LTR sequences originating from amphotropic MuLV caused nonthymic leukemias. The addition of sequences from the region of the pol-env junction of Mo-MuLV enhanced the leukemogenic potential conferred by the Mo-MuLV LTR. A similar approach to defining the molecular basis of disease specificity was taken by Chatis et al, '~ Hybrid DNA gun,rues were constructed from the molecularly cloned DNA of Mo-MuLV and F-MuLV. The recombinant viruses generated from these DNA hybrids were inoculated into newborn NFS/n mice. The forms of leukemia induced by the recombinant viruses were correlated with their gun,me structure, which was determined by oligonucl9 sequence analysis and restriction mapping. As expected, the parental Mo-MuLV and F-MuLV strains almost invariably induced thymic neoplasms and erytlaroleukemia, respectively. However, one recombinant virus which acquired most of its gun,me from F-MuLV but derived 621 3'-terminal nucleotides from Mo-MuLV was found to cause predominantly thymic disease.'* The Mo-MuLVderived sequences included the Y-terminal 99 nucleotides of the P 15(E)-coding region of the env gene, plus the entire U, region and the first 36 nucleotides of the R region of the Y.terminal repeat. A later study demonstrated that recombination with an even smaller fragment of the Mo-MuLV gun.me is sufficient to impart to F-MuLV the ability to cause thymic malignancies." This fragment measured 380 nucleotidcs in length and represented the U3 region only. These findings comprise additional evidence that the U3 region of the 3'.terminal redundant sequences of the gun,me of leukemogenie MuLVs encodes determinants of the organotrol~ism or disease-slrecificity as well as of the leukemogenicity of these viruses. The gp70- and plS(E)-coding domains of the envgene are not the only regions where the genomes of the MCF viruses differ from those of their ecotropic parental viruses. .

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Comparative oligonucleotide mapping of the genomes of the ecotropic endogenous virus Akv and the MCF viruses which arise during leukemogeaesis in AKR or (AKR • NZB)F, hybrid mice has revealed additional differences in the U~ region of the 3'-terminal redundant sequence. '~-6~ The expression of sequences which are not derived from Akv in the U3 region of the MCF virus genome correlates with leukemogenicity, as is aIso true for the 5" portion of the gp70-coding domain and the 3' portion of the plS(E)-coding domain of the env gene. Independent expression of sequences not derived from Akv has been observed in all three of these regions in the genomes of recombinant viruses isolated from the thymuses of prr AKR mice. '~'.''' The independent expression of MCF virus-related sequences in the U~ region of "~hegenome implicates this region in the determination of leukemogenicity and suggests that the po[ytropic viruses isolated from leukemic AKR mice are generated by recombination events involving three or more distinct segments of the viral genome. Similar conclusions have been reached from analysis of the recombinant viral genomes formed during the developmem of thymie malignancies in HRS/J mice, Both ecotropic and at least two classes of polytropie recombinants were recovered, suggesting that recombination may occur at three or more siteswithin the env gene. #~' Leukemogenic sequences encoded within the env gene and U, region are not derived from the ecotropic endogenous parental viruses Emv-I and Emv-3. These sequences are expressed independently. These findings provide further evidence for the occurrence of a precise sequence of recombination events among ecotropic and xenotropic endogenous virus genomes during leukemogenesis. In recent experiments by Holland et al., ~6~.~6' the Akv-derived MCF 247 virus itself served as the source of nonecotropic sequences for in vitro recombination with the Akv genome. Hybrid DNA genomes were constructed from the molecularly cloned DNA of Akv and MCF 247 virus. The infectious recombinant viruses recovered from transfection of the hybrid genomes into cultured NIH 3T3, SC-I, or MCT murine cells were assayed for leukemogenicity in newborn AKR/J, AKR/N, or NFS/n mice. The leukemogenicity data were correlated with the genome structure of the recombinants, which was determined by oligonucleotide sequence anatysis and restriction mapping. MCF 247 virus is leukemogenic in AKR mice but not in NFS mice," while Akv is not leukemogenic in any of the mouse strains ~sed. Recombinant viruses deriving only the plS(E)-coding region of their envgene from MCF 247 virus, and the remainder of their genome from Akv, were not leukemogenic, gecombinants which acquired either the gp70-coding region of their ~negene or their 3'-terminal redundant sequences (but not both) from MCF 247 virus were found to be only weakly [eukemogenic. However, recombitiant viruses containing both the p lS(E)-r sequences and the Y-terminal redundant sequences of the MCF 7.47 virus were moderately leukemogenic. An even higher incidefice of leukemia was induced by recombinants containing the gp70-coding region in combination with the 3'-terminal redundant sequences of MCF 247 virus. Recombinant viruses acquiring their entire env gene as well as their Y-terminal redundant sequences from MCF 247 virus did not induce a significantly greater incidence of leukemia than recombinants in which the plS(E)-coding region of the env gene (as well as the gag and pol genes) was derived from Akv. However, the addition of the MCF 247 virus-derived plS(E)-eoding sequences was found to shorten the latent period for leukemogenesis. In all cases, leukemogenicity correlated with the recovery of high titers of infectious recombinant viruses from the thymuse~ of infected mice. Not surprisingly, recombinant viruses tested for leukemogenicity in both AKR and NFS mice were invariably found to be more leukemogenic in the AKR strain, reflecting the pattern exhibited by MCF 247 virus. ~6~ The insights gained from studies of the !eukemogenicity of molecularly cloned subgenornic fragments of F-MuLV and amphotropic strains of MuLV, and from re-

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striction mapping and sequence analysis of the env genes of F-MuLV and Fr-MCFV led Oliff et al. '~ to construct hybrid DNA genomes derived from F-MuLV, amphotropic MuLV clone 4070, and Fr-MCFu in order to analyze further the determinants of leukemof'enicity wit it,in the F-MuLV and Fr-MCFV genomes. As in their earlier studies, the hybrid genomes were constructed by ligating specific subgenomic fragments of molecularly cloned DNA. The DNA hybrids were then transfected into cultured NIH 3T3 murine fibroblasts. The recombinant viruses recovered from the transfected cells were assayed for leukemogenicity in vivo. As expected, F-MuLV was invariably leukemogenic, with a latent period of 6 to 8 weeks, while the amphotropic MuLV was nonpathogenic. Fr-MCFV induced leukemia in 50o/o of inoculated mice with a disease latency of approximately 12 weeks. A recombinant virus designated A/Fr ENV, in which the envgene of Fr-MCFV was substituted for the corresponding region of the amphotropic MuLV genome, was found not to be leukemogenic. Other recombinants in which either the 3'-terminal redundant sequence of F-MuLV (L~) or the p lS(E)-codiag region of the env gene plus the 3'-terminal redundant sequence of Fr-MCFV (A/Fr LTR) were substituted for the corresponding regions of the amphotropic MuLV genome were likewise not leukemogenic (Figure 4). Thus, neither the env gene of Fr-MCFV nor the 3'-terminal redundant sequences of F-MuLV or Fr-MCFV are by themselves capable of causing leukemia if the remainder of the genome contains no other determinants of leukemogenicity. However, when both the env gene and the Us region of the LTR of Ihe Fr-MCFV genome were substituted for the corresponding regions at the 3' end of the amphotropic MuLV genome, the recombinant virus derived from this construct (A/Fr E+L), caused erythroleukemia in I4% of inoculated mice after a maximum latency of 6 months. The L~ recombinant virus, constructed by substituting the env gene of Fr.MCFV and the Uj region of the LTR of F-MuLV/or the corresponding regions of the genome of amphotropic MuLV, was leukemogenic in 38ot0 of inoculated mice with a similar latent period. In all cases, the eco-, poly-, or amphotropism of the recombinant viruses was specified by the tropism of the parental virus strain contributing the env gene. A!I of the recombinants derived their gag gene from the parental amphotropic MuLV and thus shared the N-tropism ot that virus. This study helped to define the nature of the sequences outside the env gene which are required for the full expression of the leukemogenic potential of F-MuLV. These additional determinants of leukemogenicity are encoded within the U~ region of the terminal redundant sequences of the F-MuLV and Fr-MCFV genomes. Nucleotide sequencing of the LTR regions of the cloned DNA genomes of three FrMCFV isolates ~2e and comparison with sequence data from other MCF viruses and various ecotropic MuLVs have recently demonstrated the presence of significant structural variations in the Us region. These variations appe~tr to correlate with the ability of a virus to induce erythroleukemia (F-MuLV and Fr-MCFV) or thymic malignancies (Mo-MuLV and Moloney MCF virus), and suggest that the U~ region of the MCF virus genome as well as that of the MuLV genome participates in the determination of organotropism or disease specificity, s20 J. The sag-pol Region The gag and pol genes of several strains of MuLes have been shown to contribute

to the [eukemogenicity of these strains. This was first demonstrated in two radiation leukemia viruses isolated from lymphoid cell lines which had been established from Xray-induced thymomas of C57BL/Ka mice, ~Q"These viruses arose by spontaneous recombination between endogenous ecotropic and xenotropic parental MuLV strains. The genomes of these recombinant viruses possess a region ol variable length overlapping the junction of the gag and pol genes which was derived from the xenotropic parental stain. The remainder of the genome was shown by restriction mapping to be

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similar to that of the ecotropic parent. The recombinant viruses are more highl~r Icukemogenic than the ecotropic parental strain, suggesting that the gag-pol regior, is at least partially responsible for their enhanced leukomogenic potential. MCF viruses also arise by recombination between ecotropic and xenotropic MuLVs. However, MC~ viruses possess a recombinant env gene, while the gag-pol-recombinant radiation le~ikemia viruses retain the ear gene, and therefore the host-range specificity of their ecotropic parent. Additional evidence for the leukemogenicity of the MuLV gag and pol genes r provided by analysis of recombinants constructed in vitro from MCF 247 virus an~:t its ecotropic endogenous parent, Akv. z~7A recombinant virus whose genome contains the gag and pol genes, the p lS(E)-coding region of the ear gene, and the 3'-terminal redundant sequences of the parental MCF virus induced thymic lymphomas in 82~,~ of AKR mice and 23% of NFS mice within 6 months after neonatal inoculation. In c:'~ntrast, the incidence of thymic disease was only 65% and 15%, respectively, for a sec,~r~d recombinant whose MCF virus-derived sequences are limited to the p lS(E)-coding t~'egion and the 3'-terminal repeat. Similar observations were made using recombinants constructed from F-MuLV, FrMCFV, and a nonleukemogenic amphotropic MuLV. 459 As noted earlier, F-MuLV is known to induce a rapidly fatal erythroleukemia in 100% of NIH Swiss mice within 8 weeks after inoculation, while Fr-MCFV is leukemogenic in 50% of animals with ~ maximum disease latency of 12 weeks. A 5.8 kbase pair DNA fragment containing the gag and pol genes of F-MuLV was ligated to a portion of the amphotropic MuLV DNA genome containing the env gene and the 3'-terminal LTR. The recombinant virus (F/A E+L) generated from this DNA hybrid induced leukemia in 20% of mice within 6 months after inoculation (Figure 4). Thus, the gag and polgenes of F-MuLV are able to confer a low degree of leukemogenicity on the ordinarily nonpathogenic amphotropic MuLV. Another recombinant virus (designated F/Fr ENV), constructed by substituting the eav gene of Fr-MCFV for that of F-MuLV, was found to cause leukemia in 46% of mice within 12 weeks after inoculation. In contrast, the L, recombinant, which derives its gag and pol genes from amphotropic MuLV, its env gene from FrMCFV, and its 3'-terminal redundant sequence from F-MuLV, induced leukemia in 38% of mice within 6 months (Figure 4). The decreased incidence of leukemia and the prolonged disease latency associated with the substitution of the gag and pol genes of the amphotropic MuLV for those of F-MuLV provide further evidence that the gag and pol genes of F-MuLV and Fr-MCFV encode determinants of leukemogenicity which are absent from the corresponding regions of the amphotropic MuLV genome. VII. CONCLUSIONS Molecular cloning techniques have succeeded in identifying four discrete regions within the murine leukemia virus genome which encode determinants of Ieukemogenicity. These are (1) the U, region of the 3'-terminal redundant sequence, (2) the 5' portion of the gp70-coding domain of the env gene, (3) the 3' portion of the pl5(E)coding domain of the enr gene, and (4) the 8ag-pol region. Many instances of murine viral leukemogenesis are accompanied by recombination, within one or more of these regions, between ecotropic MuLVs and endogenous viral sequences. The resulting recombinant viruses (MCF viruses) generally exhibit a polytropic host range and may act as the ultimate leukemogenic agents in rico. The individual contributions of the leukemogenic regions of the MuLV and MCF virus genomes to t~e expression of the leukemogenic phenotype appear to be additive, since various spontaneously occurring or in vitro-generated recombinant viruses which contain one, two, or three of these changes are intermediate in leukemogenicity relative to their parental strains.

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The molecular, mechanisms by which the viral genetic determinants of leukemogenicity mediate the process of leukemogenesis remain speculative. Our current understanding of these mechanisms is deduced from studies of the structure and expression of the MuLV genome, and from investigations of the properties of routine leukemia ceils. Thus, the Ua region of the 3'-terminal redundant sequence may act by promoting or enhancing the transcription of other integrated viral sequences or of cellular ontogenes near the integrated provirus. Both the Ua region and the envgene play a role in the determination of viral host range and organotropism. The latter property appears to determine the type of disease caused by a given MuLV isolate. These genetic determinants of the target cell population for a given virus likely influence leukemogenicity by controlling the ability of the virus to establish infection of specific hematopoietic cells and to spread throughout the host animal once productive infection has been established. The nature of the contributions of the gag and pol genes is suggested by the mapping of N- and B-tropism within the p30-coding region of gag, and by the association of a DNA endonuclease activity with the primary product of the polgene (reverse transcriptase). This endonuclease, which is capable in nicking the LTR region of viral DNA, may be required for preparing the provirus for integration. Future research will focus on these hypothesized mechanisms for the involvement of MuLV gene products in leukemogenesis. Other studies will continue to explore the cellular aspects of leukemngenesis, emphasizing virus-induced changes in cellular oncogene expression and in growth-factor regulation of cell proliferation and differentiation. Finally, while leukemogenic retroviruses are considerably more widespread in mice than in humans, the near universality of cellular oncogenes indicates that the viral ]eukemias of mice, as well as the neoplasms induced by acutely transforming retroviruses, will continue to provide important model systems for the experimental investigation of the mechanisms of human carcinogenesis,

REFERENCES 1. Abelson, H. T. and Rabstein, L. S., Influenceof prednisoloneon Moloneyleukemogenicvirus in BALB/cmice, Cancer Res., 30, 2208, 1970. 2. Abelson,H. T. and Rabstein, L. S., Lyrnphnsarcoma:virus-inducedthymic-independentdiseasein mice, CancecRcs.,30, 2213, 1970. 3. Adams,L M., Gerondukis,S., Webh,E., Mitchell, J., Bernard,O., and Cory, S., Transcriptionally active DNA region that rearrangesfrequentlyin murinelymphoidtumors, Proc. Natl. Acad. SeL U.S.A., 79, 6966,1982. 4. All, M. and Baluda,M. A., Synthesisof avianoncoranvirusDNA in infectedchickencells, J. ViroL, 13, 1005,1974. 5. Andersen,P. R., Devarr S. G., Tronick,S. R., Ellis, R. W., Aaronson,S. A., and Scolnick,E. M., Generationof BALB-MuSVand Ha-MuSVby typeC virustransductionof homologoustransforming genes fromdifferentspecies, Cell, 26, 129, 1981. 6. Andersson,P., Goldfarb,M. P., and Weinberg,R. A., A defined subsenomicfragmentof in vitro synthesizedMoloneysarcomavirusDNAcan inducecelltransformationupon transfection, Cell, 16, 63, 1979. 7. Andrews,J. M. and Gardner,M. B., Lowermotorneurondegenerationassociatedwithtype-CRNA virus infectionin mice:neufopathologicalfeatures, J. Neuropathol. ~xp. Neurol., 33,285,1974. 8. Anki, T., Potter, M., Sturm, M" M., Lie. M., and Walling, M. J., Cell populations and known surface antigens of tumors inducedby Abelsonvirusin pristane.primedBALB/emice: an analysis by immunoelectronmicroscopy,I. Natl. Cancer Inst., 55, 1097, 1975. 9. A1cement, L. J., Kin'shin0 W. L., Ha~o, R. B., and Arlinahaus, R. B., "gag" polyprotein precursors of Rauschermurineleukemiavirus, Virology, 81,284, 1977.

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C R C Critical R e v i e w s in O n c o l o g y / H e m a t o l o g y

10, Arcemeat, L. J., Karshin, W. L., Naso, R. B , Jamjoom, G., and Arlinghaus, R. B., Biosynthesis of Rauscher leukemia viral proteins: presence of p32 and envelope pJ 5 sequences in precursor polypcptides, Virology, 69, 763, 19'76. 11. Armstrong, M. Y. K., Weininger, R. B., Binder, D., Himsel, C. A., and Richards, F. F , Role of endogenous leukemia virus in immuanlogically triggered lymphoreticular tumors. IL Isolation of Btropic mink cell focus-lnducing (MCF) routine leukemia virus) Virology, 104, 164, 1980. 12. August, J. T., Bolognesi, D. P., Fleissner, E., Gilden, R. V., and Nowlnski, R. C., A proposed nomenclature for viriou proteins of oucogealc R N A viruses, Virology, 60, 595, ! 974. 13. Axelrad, A. A., Croizat, H., and Eskinazi, D., A washable macromolecule from Fv2" marrow negatively regulates DNA synthesis in erythropoletin progenitor cells BFU-E, Ceil, 26,233, 1981. 14. Axelrad, A. A. and Steeves, K. A., Assay [or Friend leukemia virus: rapid quantitative method based on enumeration of macroscopic spleen loci in mice, Virology, 24, 513, 1964. 15. Axe[tad, A; and Van des Gang, H. C., Genetic and cellular basis of susceptibility or resistance to Friend leukemia virus inf~ctlon in mice, Can. Cancer CoaL, 8, 313, 1969. 16. Baeheler, L. T. and Fan, H., Multiple integration sites for Moloney murine leukemia virus in productively infected mouse fibroMasts, J. Virol., 30, 657, 1979. 17. Bacheler, L. T. and Fan, H., Integrated Moloney murine leukemia virus DNA studied by using complementary DNA which does not recognize endogenous related sequences, J. Virol., 33, 1074, 1980. 18. Bader, J. P., The role of DNA in the synthesis of Rous sarcoma virus, Virology, 22, 462, 1964. 19. Bades, J. P. and Steck, T. L., Analysis of the ribonucleic acid of murine leukemia virus, J. Virol., 4, 454, 1969. 20. Balduzzi) P. C., Mechanism of oncogenic transformation by Rous sarcoma virus. Ill. Role of proviral DNA in morphologic conversion of chiCken embryo firbroblasts, J. ViroL, 12, 284, 1973. 21. Ball, J. K., Harvey, D., and McCarter, J. A., Evidence for naturally occurring routine sarcoma virus,

Nature (London), 241,272,1973. 22. Baltimore, D., RNA-depeedent DNA polymerase in virlons of RNA tumour viruses, Nature (Lon. don), 226, 1209, 1970. 22. Baltimore, D., Tumor viruses: 1974, Cold Spring Harbor Syrup. Quant. Biol., 39, 1187, 1974. 24. Baltimore, D., Shields, A., Otto, G., Golf, S., Besmes, P., WiRe, O., and Rosenberg, N., Structure and expression of the Abelson murinc leukemia virus genome and its relationship to a normal cell gene, Cold Spring Harbor Syrup. Quant. Biol., 44, 849, 1979. 25. Baluda, M. A. and Nayak, D. P., Incorporation of precursors into ribonueleic acid, protein, glycoprotein, and llpoproteln of avian myeloblastosis virions, J. Virol., 4, 554, 1969. 26. Barbaeid, M., Robbins, K. C., and Auroason, S. A., Wild mouse RNA tumor viruses. A nongenetically transmitted virus group closely related to exogenous leukemia viruses of laboratory mouse strains, J. Exp. Med., 149, 254, 1979. 27. Barbaeid, M., Stephenson, J. R., and Aaronson, S. A., gaggene of mammalian type-C RNA tum~>ur viruses, Nature (London), 262, 554, 1976. 28. Barbacid, M., Troxler, D. H., Scolnick, E. M., and Auronson, S. A., Analysis of translational products of Friend strain of spleen focus-forming virus, J. Virol., 27, 826, 1978. 29. Barbiesi-Weil[, D., Mathieu-Mahul, D., Gay, F., Robert-Lezenes, $., Mureau-Guchelin, F.) Wendling, F., Laanmbe, C., Casadeval[, N., Tambourin, P.) and Lursen, C. J., Genesis of a new spleen focus-forming virus: possible role of MCF viruses, Virology, 12g, 234, 1983. 30. Russia. R. H , RuscettJ, S., All, I., Haapala, D. K., and Rein, A., Normal DBA/2 mouse cells synthesize a glycoprotein which interferes with MCF virus infection, Virology, 123, 139, 1982. 31. Battula, N: and Temln, H. M., Infectious DNA of spleen necrosis virus is integrated at a single site in the DNA of chronically infected chicken fibrob|asts, Pron. Natl. Acad. Sci. U.S.A., 74, 281,1977. 32. Battula, N. and Temin, H. M.~ Sites of integration of infectious DNA of avian reticuloendothellosis viruses in different avian cellular DNAs, Cell, 13,387, 1978. 33. Bazill, G. W., Haynes, M., Garland, J., and Dexter, T. M., Characterization and partial purification of a haemopoietic ceil growth factor in WEHI-3 cell conditioned medium, Biocltem. J., 210, 747, 1983. 34. Benade, L. E. and Barbacid, M., Polymurphism among the major core proteins of C57BL B-tropic murlne leukemia viruses, Virology, 106, ~tgT,1980. 35. Benade, L. E. and lhle, d. N., Different serotyp~s of B-tropic murine leukemia viruses and association with endogenous ecotropic viral Iocl, Virology, 106, 374, 1980. 36. Benade, L. E., lhle, J. N., and l~cleve, A., Serological characterization of B-tropic viruses of C57BL mice: Possible origin by recombination of endogenous N-tropic and xenotropic viruses, Pron. NarL Acad. Sci. U.S.A., 75, 4553, 197g. 37. Bender, W., China, Y.-H.,.Chattopl~hyay, S., Vogt, P. K., Gradner, M. B., and Davidson, N., Hi,,h-molecular-weight RNA$ of AKR, NZB, and wild mouse viruses and avian reticuloendothelioais virus till have similar dimer structures, 3". ViroL, 25,888, 1978.

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38. Bennett, M., Stccves, R. A., Cudkowicz, G., MJrand, E. A., and Russell, L. B., Mutant S/alleles of mice affect susc~plibility to Friend spleen focus-fvrming virus, Science, 162, 554, 1968. 39. Bentvelzen, P,, Aarssen, A. M,, and Brinkhof, J., Defect~vity of Rauscher murine e~-ythroblastosis virus, Nat. (London), N. BioL, 239, i 22, 1972, 40, Benz, E. W., Jr. and Dina, D.~ Molortey routine sarcoma virions synthesize full-gcnome..length double-stranded DNA in vitro, Proc. Natl. Acad. Sci. U.S.A,, 76, 3294, I979, 41. Benz, E. W., Jr., Wydro, R. W., Nadat-Ginard, B., and Dina, D., Moloney routine sarcoma proviral DNA is a transcriptional unit, Nature (London), 288, 665, 1980. 42. Bernstein, A., Gamble, C., Pentos~, D., and Mak, T. W., Present= and expression of Friei~d erythroleukemia virus-related sequences in normal and leukemic mouse tissues, Proc. Natl. Acafl. Sci. U.S.A., 76, 4455, 1979, 43. Bernstein, A., Mak, T. W., and Stephenson, J. R., The Friend virus genuine: evidence fer ~he stable association of MuLV sequences and sequences involved in erythro]eukemic transformation, Cell, I2, 287, 1977. 44, Bishop, J. M., Celhtlar oncogenes and retroviruses, Annu. Bey. Biochem., 52, 301, I983. 45, Blair, D. G., McClements, W. L., Oskarsson, M, K., Fischinger, P. J,, and Vande Woudr G. F., Biological activityof cloned Moloney sarcoma virus D N A : terminally redundant sequences may enhance transformation efficiency, Proc, Ned. Acad. $ci. U.S.A., 77, 3504, 1980. 46. Roircn, M., Levy, J.-P-, Lasncret, J., Oppenheim, S.) and gerr~,rd, L, Palhogenes[s of Rauscher leukemia, d. Natl. Cancer Inst., 35, 865, 1965. 47, Bolognesi, D. P., Lufti$, R., and Shaper, J. H,, Localization of RNA tumor virus polypeptides. I. Isolation of further virus substructures, Virology, 56, 549,1973, 48. Bondurant, M., Hashimoto, S.-I., and Green, M., Methylation pattern of genomic RNA from Moloney murine leukemia virus, 1. Virol., 19, 998, t976. 49. Boss, M., Greaves, M., and Teich, N., Abelson virus transformed haematopoietic cell lines with preB-cell characteristics, Nature (London), 278, 551,1979. 50. BosseIman, R. A., Van Griensven, L. J. L. D., Vogt, M., and Verma, I, M., Genuine organization of retrovir~ses. VI. Heteroduplex analysis of ecotropir and xenotropic sequences of Moloney mink cell foc~s-ind~cMg viral RNA o~tained from either a clct~ed isolate or a thymvrna ceil lithe, J. Virol., 32,968, 1979. 51. Bosselman, R. A., Van Griensven, L. J. L. D., Vogt~ M., and Verma, I. M., Genuine organization of retroviruses. IX. Analysis of the genomes of Friend spleen focus-forming {F-SFFV) and helper murine leukemia viruses by heteroduplex.formation, Virology, 102, 234, 1980. 52. Bosselman, R. A., van Straaten, F., Van Beveren, C., Verma, !. M., and Vogt, M., Analysis of the env gene of a molecularly cloned and biologically active Moloney mink ceil focus-forming proviral DNA, jr. ViroL, 44, [9, 1982. 53. Bosselman, R. A. and Verma, 1. M., Genome organization of retroviruses. V. In vitro.synthesized MoJoney murine leukemia viral DNA has long terminal redundancy, J. Virol., 33,487, 1980. 54. Boyse, E. A. and Old, L. 3., A comment on the genetic data relating to exp:~ssM~ of TL antigens, Transplaotaffon, 11,561, 1971. 55. Bruggr J. S. and Erikson, R. L., Identification of a transformation.specific antigen induced by an avian sarcoma virus, Nature (London), 269, 3,'.6, 1977. 56. Brugge, J. S., Putchio, A. F., and Edkson, R, L., Virus-specific RNA species present in the cytoplasm of Rous sarcoma virus-infected chicken cells, Virology, 83, 16,1977. 57. Brugge, J. S., Purchio, A. F., and Erikson, R. L., The distribution of virus-specific RNA in Rous sarcoma virus-induced hamster tumor ceils, Virology, 83, 27, 1977, 38. Bryant, M. L. and Klement, V,, CIonal heterogeneity of wild mouse leukemia viruses: host range and antigenieity, Virology, 73, 532, 1976. 59. Bryant, M. L., Pal, B. K,, Gardner, M. B., Elder, J, H,, Jensen, F. C., and Lerner, R. A., Strttctura! analysis of the major envelope glycoprotein (gpTO) of the amphotropic and r type C viruses of wild mice, Virology, 84, 348, ~97g. 60. Buchhagcn, D. L., Pedersen, F, S., Crowthcx, R. L., and Hascltine, W. A., Most sequence differenccs betw~n the senomes of the AKV virus and a leu~kemogenic Gross A virus passaged in vitro a r e located neat the 3' terminus, Proc. Natl. Acad. Sci. U.g.A,, 77, 4359, 1980. 61, Buffett, R. F. and Furth, J., A transplantable reticulum-cell sarcoma variant of Friend's viral leukemia, Cancer Res., 19, 1063, 1959. 62. Canmmi, E. and Aatonson, S, A,, Rest:iction enzyme analysis of mouse cellular type C viral DNA: emergence of new viral sequences in spontaneous AKR/J lymi~homss, Proc. Natl. Acad. ScL U.S.A., "}6, t6"/7, I979. 63, Canaani, E. and Duesbcr$, P., Role of subunits of 60 to 70S avian tumor vir~s ~ibonueleic acid in its template activity for the viral deoxyribonucleic acid polymerasr J. Virol., 10, 23, ;972, 64. Canam~i, E., Dued~erll, P., and Dine, D,, Cleavage map of linear mome sarcoma virus DNA, Proc. Natl. Ae=d. $ci. U,$.A., 74, 29, 1977,

296

C R C Critical Reviews in O n t o l o g y ~ H e m a t o l o g y

65. Canaani, E., Robb_;ns, K. C., and Aaronson, S. A., The transforming gene of Moloney marine sarcoma virus, Nature (London), 282, 378, 1979. 66. Chart, H. W., Garon, C. F., Chang, E. H., Lowy, D. R., Hagen, G. L., Scolnick, E. M., Repaske, R., and Martin, hi. A., Molecular cIooing of the Harvey sarcoma virus circular DNA intermediates. IL Further structural analyses, J. Virol., 33, 845, 1980. 67. Chang, E. H., Furth, M. E., Scolnlek, E. M., and Lowy, D. R., Tumourigenic transformation of mammalian cells induced by a normal human gene homologous to the oneogeae of Harvey routine sarcoma virus, Nature (London), 297,479, 1982. 68. Chang, E. H.) Moryak) J. M., Wei, C.-M., Shlh, T. Y., Shober, R., Cheung, H. L., Ellis, R. W., Hager, G. L., Scolnick, E. M., and Lowy, D. R., Functional organization of the Harvey routine sarcoma virus genuine, J. Virol.,35, 76, 1980. 69. Chang, K. S. S.) Aoki, T., and Law, L. W., Isolation of B-tropic type.C virus frbm reticulum cell neoplasms induced in BALB/c miee}py SJL/J type-C virus, J. Natl. Caacar Inst., 54, 83, 1975. 70. Chaffs, P. A., Holland, C. A., Hartley, J. W., Rowe, W. P., and Hopkins, N., Role for the 3' end of the genuine in determining disease specificity of Friend and Moloney murine leukemia viruses, Proc. Natl. Anna. ScL U.S.A., 80, 4408, 1983. 71. Chatis, P. A., Holland, C. A., Silver, J. E., Frederickson, T. N., Hopkins, N., and Hartley, J. W., A 3' end fragment encompassing the transcriptional enhancers of hondo(active Friend virus confers erythroleukemogenicP;y on Moloney leukemia x,irus, J. Virol., 52, 248, 1984. 72. Chattopadhyay, S. K., Cloyd, M. W., Linemeyer, D. L., Lander, M.R., Roods, E., and LOWy, D. R., Cellufar origin and role of mink cell focus-forming viruses in murine thymlc lymphomas, Nature (London), 295, 2S, 1982. 73. Chaff.opadhyay, S. K., Hartley) J. W., Lander, M. R., Kramer, B. S., and Rowe, W. P., Biochemical characterization of the amphotropie group of murlae leukemia viruses, J..Virol., 26, 29, 1978. 74. Chattopadhyay, S. K., Lander, M. R., Gupta, S., Hands, E., and Lowy, D. R., Origin of mink cytopathie focus-forming (MCF) viruses: comparison with ecotropic and xeootropic murlne leukemia virus genomes, Virology, 113,465, 1981. 75. Chattopadhyay, $. g., Lender, M. g., and Rowe, W. P., Close similarity between endogenous contropic virus of Mus musuulus molossinusand AKR virus, J. Virol., 36, 499, 1980. 76. Chattopaglhyay, S. K., Low'/, D. R., Teich, N. M., Lupine, A. S., and Rowe, W. P., Evidence that the AKR routine-leukemia-rims genuine is complete in DNA of the high-virus AKR mouse and incomplete in the DNA of the "virus-negative" NIH mouse, Pron. NatL Acad. 5ci. U.&A., 71,167, 1974. 77. Chesebro, B., Portis, J. L,, Wehrly, K., and Nishio, J., Effect of routine host genotype on MCF virus expression, latency, and leukemia cell type of leukemias induced by Friend routine leukemia helper virus, Virology, 128, 22l, 1983. 78. Chesebro, B. and Wehfly, K., Rfv-I and Rfv-2: two H-2-associated genes that influence recovery from Frieud leukemia virus-ind',~r splenomegaly, J. Immunol., 120, 1081, 1978. 79. Chesebro, B. arid Wehrly, K., Identification of a non-H-2gene (Rfv.J)influencing recovery from vitamin and leukemia induced by Friend virus complex, Proc. Natl. Acad. Sci. U.S.A., 76, 425,1979. 80. Chesebro, B., Wehrly, K., Doig, D., and Nishio, J., Antibody-induced modulation of Friend virus cell surface antigen decreases virus production by persistent erythrolenkemla cells: influence of the Rfv-3 gene) Pron. Natl. Acad. gel U.S.A., 76, 5784) 1979. gl. Chesebro, B., Wchrly, K,, Nishio, J., and Evans, L., Leukemia induction by a new strain of Friend mink cell focus-lnducing virus: synergistic effect of Friend eeotropin routine leukemia virus, J. Virol., 51, 63, 1984. 82. Chesebro, B., Wehrly, K., and Stimptling, J. H., Host genetic control of recovery from Friend leukemia virus-induced splenomegaly, Mapping of a gene within the major histocompatihility complex, ./. Exp. Mud., 140, 1457, 1974. 83. Chien, Y.-H., Verma, I. M., $hih, T. Y., Scolnick, ~. M., and Davidson, N., Heterodnplex analysis of the sequence relations between RNAs of mink cell focus-inducing and murine leukemia virt~ses, Y. Virol.,28, 352~ 1978. g4. Chirigos, M. A., Scott, D., Turner, W., and Perk, K., Biological, pathological and physical characterization of a possible variant of a routine sarcoma virus (Moloney), lot. J. Cancer, 3,223, 1968. gS. Clark, S. P. and Mak, T. W., Complete nucleotide sequences o[ an infectious clone of Friend spleen focus-forming provirus: gp55 is an envelope fusion glycoproteln, Pron. Natl. Acad. gel. U.S.A., 80, 5037, 1983. 86. Clarke, B. J., Axelrad, A. A., Shreevr M. M,, and McL~,--od, D. L., Erythroid colony induction without erythropoietin by Friend leukemia virus in vitro, Proc. Natl. Acawl. Sci. U.S.A., 72, 3556, 1975. 87. Cloyd, M. W., Hartley, J. W., and Rowe, W. P., Lymphomagenicity of recombinant mink cell focus. inducing routine leukemia viruses, J. Exp. Mad., 151, g42, 1980.

V o l u m e 5, Issue 3

297

88. Cloyd, M. W., Hattley, J. W., and Rowe, W. P., Genetic study of [ymphoma induction by AKR mink cell focus-ir~ducin8 murine leukemia virus in AKR x NFS crosses, I. Exp. Med., 154, 450,1981. 89. Coffin, J. M., Structure, replication, and recombination of rctrov[rus genorr:,es: some unifying hypo'~he~es, J. Gen. Virol.,42, I, 1979, 90. Coffin, 3. M, and Billeter, M, A., A physical map of the Rous ~arcoma virus genorne, J. Mol. Biol., 100, 293, 1976, 91. Coffin, J. M., Hageman, T. C., Maxam, A. M., and Haseltine, W. A,, Structure of the ~enome of Moloney marine leukemia virus: a terminally redundant sequence, Cell, 13,761,1978. 92. Coffin..I.M. a~d Hasetti~e, W. A., Terminal redundancy and the origin of replication of Rous sarcoma virus gilA, Proc. Natl. Acad. Sci. U.S.A.,';a, 1908, 1977. 93. Coffin, J. M., Parsons, 2. T., Rymo, L., Haroz, R. K., and Weissmann, C., A new approach to the isotation of RNA-DNA hybrids and its application to the quantitative determination of labeled tumor virus RNA, J. MoL Biol., 86, 373, 1974. 94. Cohen, J. C., Shank, P. R,, Morris, V. L., Cardiff, R., and Varmus, H. E., Integration of the DNA of mouse mammary tumor virus in virus-infected normal and neoplastic tissue of )he mouse, Cell, 16, 333,1979. 95. Collett, M. S. and Erikson, R, L,, Protein kinase activity associated with the avian sarcoma virus see gene product, Proc. NaiL Acad. Sci. U.S.A., 75, 2021,1978, 96. Cooper, G. M., Cellular transforming genes, Science, 218, 801,198L 97. Cooper, G. M. and Nr P. E., T~no distinct candidate transforming gene~ of 13)mphoid ~eukosis virus-induced neoplasms, Nature (London), 292, 857,1981. 98. Copeland, N. G, and Cooper, G. M., Transfection by exogenous and endogenous marine retrovirus DNAs, Ceil, 16, 347, 1979. 99. Copeland, N. G., Zelenetz, A. P., and Cooper, O. M., Transformation by subgenomic fraglnents of Rous sarcoma virus DNA, r ! 9, 863,1980. 100. Corcoran, L. M., Adams, J. M., Dunn, A. ll., and tory, S,, Marine T lymphomas in which the cellular myconcogene has been activated lay retroviral insertion, Cell, 37, 113, 1984. 101. Cordell, B., Weiss, S. R., Varmus, II, E,, and Bishop, J. M,, At least 104 nucleotides are t~ansposed from the 5' terminus of the aviar, sarcoma virus gertome to the 5' termini of smaller viral mgNAs, Cell, 15, 79,1978. 102, Crews, $, Barth, R., Hood, L., Prehn, J., and Calame, g., Mouse c-mye oncogenr is located on chromosome 15 and translocated ~o chromosome 12 in plasmacytomas, Science, 218, 1319, 1982. 103. Cuypers, H. T., Selten, G., Quint, w.. gijlstra, M,, Robanus Maanday, E,, Bodens, W., van Wezenbeek, P., Mailer, C., and Barns, A., Marine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region, Ceil, 37,141, 1984. 104, Czernilofsky, A. P., DeLorbe, W., Swanstrom, g., Varmus, H. E., Bishop, J. M., Tisehet, s and Goodman, H. M., The nucleotide sequence of an untranslated but conserved domain at the 3' end of the avian sarcoma virus genuine, Nucleic Acids Res., 8, 2967, 1980. 105. Dahlberg, J. E., Harada, F,, and Sawyer, g. C.. Structure and properties of an RNA primer for initiation of Rous sarcoma virus DNA synthesig in vitro, Cold Spring Hartwr Syrup. Quant. BioI., 39, 925,1974. 106. Dahlberg, J. E,, Sawyer, R. C., Taylor, J. M., Faras, A. I., Levinson, W. E., Goodman, H. M., and Bishop, I, M., Transcription of DNA from the 70S RNA of Rous sarcoma virus. I. Identification of a specific 4S RNA which serves as palmer, J. VlroL, i3, i126, i9"14. 107. Dalla Favera, R., Gelmann, E. P., Gallo, R. C., and Wong.Staal, F., A human oncgene homologous to the transforming gene (v-sis) of simian sarcoma virus, Nature (London), 192, 31, 1981. 108. Datta, S. K,, Thomas, C. Y,, Nicklas, J, A., and Coffin, J. M., Thymic epithelial genotype influences the production of recombinant leukemogenic retroviruses in mice, J. Virol., 47, 33, i983. 109. Davis, J., Seherer, M., Tsai, W. P., and Long, C., Low-molecular-weight gauscher leukemia virus protein with preferential binding for single-stranded RNA and DNA, Jr. Virot., 18,709, 1976. 1 I0. Dawson, P. J., Dresler, S. L., and Fieldster A. H,, lmmunofluorescenee and histologic studies of virus-induced marine lymphocytic leukemias, 3. N~tL Cancer Inst., 56, 1t)47, 1976. I 11. Dawson, P. J., Dresler, S. L., and Fieldst~l, A. H., Erythroid leukemia induced by Friehd lymphatic leukemia virus in T-ceil-depleted mice, Cancer Res., ~9,1611, 1979. 112. Dawson, P. J., Fir A. H., and Bosdck, W. L., Pathologic studies of Friend virus leukemia and the development of a transl~lantable tumor in BALB/c mice, Cancer Res., 23,349, 1963. 113. Dawson, P. J., Rose, W. M., and Fieldstcr A. H., Lymphatic leukaemia in rats and mice inoculated with Friend virus, Br. J. Cancer, 20, ! 14, 1966. 114. Dayton, A. I., Selden, J, R,, Laws, G., Dorney, D. J,, Fkt~n, J,, Trippur P., Emanuel, B, $., Rovera, G., Nowr P. C., and Croee, C. M., A human c.erbA oncogene homoiollue is closely proximal to the chromosome 17 breakpoint in acute promyelocytir leukemia, Proe. Natl. Aca#. Sei. U.S.A., 81, 4495,1984.

298

C R C Critical ~eviews in O n t o l o g y ~ H e m a t o l o g y

i 15. Decleve, A., Lieberman, M., lhle, J. N., and Kaplan, H. S,, Biological and serological characteriz~tion of radiation leukemia virus, Proc, Natl. Acad. Sd. U.S.A., 73, 4675, 1976. 1I6. Declare, A., Lieberman, M., lhte, J. N., Rosemhal, P. N., Lung, M. L., and Kaplan, H. S., PhysiochemicaI, biologicaI and sero[ogicaI properties of a leukemoger~ic virus i~olatcd from cultured RadLV-induced lymphomas of C57BL/Ka mice, Virology, 90, 23, 1978, 117. Declare, A,, Lieberman, M., and Kaplan, H. S., In viva interaction between RNA viruses isolated from the C57BL/Ka strain of mice, Virology, 81,270, I977. 118. Declare, A., Niwa, O., Gelmann, E., and Kaplan, H. S,, Replication kinetics of N.and B-tropic marine leukemia viruses on permissive and nonpermissive cells in vitro, Virology, 65,320, 1975. 119. Declare, A., Niwa, O., Kojola, J., and Kaplan, H. 5., New gone locus modifying susceptibility to ceEtain B.tropic murinr leukemia viruses, Proc. Natl. Acad, Set. U.&A., 73,585, 1976. 120, OePeo, D., Gouda, M. A., Young, H. ~., Chang, E. H., Lowy, D. R,, $colnick, E, M., and Ellis, R. W., Analysis of two divergent rat gcnomic clones homologous to the transforming gone of Harvey routine sarcoma virus, Proc. Natl. Acad. $ci. U.S,A., 78, 3328, 1981. 121, DeLarr J. and Todaro, G, J., Membrane receptors for marine leukemia viruses: characterization using the purified viral envelope glycoproteJn, gp71, Ceil, 8.365, 1976. ~22. DeLorbe, W. 2., Luciw, P. A., Goodman, H. M., Cartons, H, E., and Bishop, J. M., Molecular cloning and characterization of avian sarcoma virus circular DNA molecules, ]. ViraL, 36, 50, 1980. 123. Deng, C.-T.) Stehelin, D,, Bishop, J. M., and Varmas, H. E., Characteristics of virus-specific RNA in avian sarcoma virus-transformed BHK.21 ceils and revertants, Virology, 76,313, 1977. 124. DesGros9 L., Barrette, M., and Jolicoeur, P., Physical mapping of the paralysis-inducing de. lerminant of a wild mouse ecotropic neurotropic retrovirus, J. Viral., 52,356,1984, 125. DesGroseillers, L. and Jolicoeur, P., Physical mapping of the Fv-I tropism host range determinant of BALB/c marine leukemia viruses, ,I'.ViraL, 4S, 685,1983. 126. DesOroseillers, L. and Jolicoeur, P., The tandem direct repeats within the long terminal repeat of marine leukemia viruses are the primary determinant of their leukemogenic potential, .7. ViraL, 52, 945,1984. 127. DesGrosr L. and Jolicoeur, P., Mapping the viral sequences conferring leukemogenicity and disease specificity in Moloney and amphotropic rnurine leukemia viruses, J. tiroL, 52, 448, 1984. 128. DesGrosr L., Rassarh E., and Jolicoeur, P., Thymotropism of routine leukemia virus is conferred by its long terminal repeat, Proc. Natl. Acad. gal. U.S.A., 80, 4?03,1983. i29. DesOroseillers, L., Villemur, R., and Jolicocut, P., The high leukemogenic p~tential of Gross passage A routine leukemia virus maps in the region of the genuine correspor~ding to the long terminal repeat and to the 3' end of any, I. Viral., 47, 24, ~[98J. 130. Dexter, T. M,, Allen, T, D., Testa, N. G., and Scolnick, E,, Friend disease in vitro, J. Exp. Mad., ! 54, 594, ] 981. 131. Dhar, R., McClements, W. L., Enquist, L. W,, and Vav.de Woude, G. F,, Nuclear[de sequences of integrated Moloney sarcoma pruritus long terminal repeats and their host and viral iunctions, Proc. Natl. Acad. Sci. U.S.A., 77, 3937, 1980. 132. Diekson, C., Smith, R., Brookes, S., and Peters, O., Tumorigenesis by mouse mammary tumor virus: proviral activation of a cellular gone in the common integration region int-2, Ceil, 37,529, 1984. 133, Diett, M., Fouchey, S. P., Langley, C., Rich, M. A., and Furmanski, P., Spontaneous regression of Friend virus-induced erythroleukemia. 1. The role of the he2per marine leukemia virus componem, J. Exp. Mad., 145, 594, 1977. 1:t4. Dimoek, K. ancLStoltzfus, C. M., Sequence sFecificity of internal methylation in B77 avian sarcoma virus RNA subunits, Biochemistry, 16, 471, 1977, 1:B. Dimock, K.~and Stoltzfus, C. M., Cycloleucine b|ocks 5'-terminal and internal methylations of avian sarcoma vires genuine RNA, Biochemistry, 17, 3627, 1978. t36. Dina, D., Bcemon, g., and Duesberg, P., The ~0S Moloney sarcoma virus RNA contains leukemia virus nucieotidr s~uenccs, Ceil, 9, 299. I976. 1.~7, Dina, D. a~d Be~, E. W., Jr., Sr162 of muri,~e sarcoma virus DNA replicative intermediates symhesized in vit:~, J. tirol., 33, 377, 1980. 138. Dinowitz, M., Inhibition of Rous sarcoma virus by a-amanitin: possible role of cell DNA-dependent RNA pob./merasr form 11, Virology,66,1,1975. 139. Dofuku, R,, Biedlet, J. L., Spenl0er, B. A., and Old, L. J., Trisomy of chromosome 15 in spontaneous leukemia o! AKR mice, Pror Natl. Acad. Sci. U.S.A., 7Z, 1515,1975. 140. Donehowet, L. A. and Vannus, H. E., A mutant marine leukemia virus with a single missense cation in pulis defective if, a function affecting ineegration, Proc. Natl. Acad. $r U.S,A., 81,6461, 1984, 141. Pants-Keller, H., gommelaere, J., Ellis. R. W., and Hopkins, N., Nudeotide sequences associated w/tt~ differences in ekw.trophoretic mobility of envelope t[lycoprotein gpTOan~ with O,, antigen phenotype of certain marine leukemia viruses, Proc. Natl. Acad. Yr U.S.A,, 77, 1642~ 1980,

V o l u m e 5, Issue 3

299

142. Donoghue, D. J., Rothenberg, E., Hopkins, N., Baltimore, D., and Sharp, P. A., Heteroduplex analysis of the nonhomology region between Moloney MuLV and the dual host range derivative HIX virus, Cell, 14, 959, 1978. 143. Drafter, $., Ruin, M., Mur~'ay, M. J., and Kabat, D., Glycoprotein encoded by the Friend spleen focus-forming virus, J. Viral., 30, 564, 1979. i44. Duesberg, P. H., Physical properties of Rous sarcoma virus RNA, Proc. Natl. Acad. Sci. U.S.A., 60,1511, 1968. 145. Duesberg, P. H. and Robinson, W. S., Nucleic acid and proteins isolated from the Rauscher mouse leukemia virus (MLV), Proc. Natl. Acad. Sol U.S.A., 55, 219,1966. 146. Duyk, G., Lets, J., Longlatu, M., and Skalka, A. M., Selective c|envage in the avian retrovirai Jong terminal repeti~ sequence by the endonuciease e~sociated with the ~ fozm of avian reverse transcriprage, Proc. Natl. Acad. Sol U.S.A,, 80, 6745, 1983, 147. Edwards~ S. A. and Fan, H., gag-related polyproteins of Moloney routine leukemia virus: evidence for independent synthesis of glycosylated and uoglycosylated forms, J. Viral, 30, 551, 1979. 148. Edwards, S. A. and Fan, H., Sequence relationship of glycosylalcd and ungtycosylated gag polyproreins of Moloney murine leukemia virus, J. Viral., 35, 4I, 1980. 149. Edwards, S. A. and Fan, H., [mmuv.o~elect[on arid chacacterization of Molone~ routine |eukemia virus-infected cell }ines deficient in surface gaganfigcn expression, Virology, ! 13, 95,1981. i50. Elder, jr. H., Gautsch, i. W., Jansen, F. C., Lemur, R. A., Hartley, J. W., and Rowe, W. P., Biochemical evidence that MCF murine leukemia viruses are envelope (any)gone recombinants, Proc. Nail Ace& $ci. U,S.A., 74, 4676,1977, 151. ELLis,R. W., OeFeo, D., Maryak, J. M., Young, H. A., Shah, T, Y., Chang, E. H., Lowy, D+ g., and Scoltdck, E. M., Dual evolutionary origin for the rat genetic sequence~ cf Harvey murine sarcoma vii"Us, 1. Viral, 36,408,1980. 152. Ellis, R. W., DeFeo, D., Shah, T. Y., Panda, M. A., Young, H. A., Tsuchida, N., Lowy, D. R., and Scolnick0 E. M., The p21 srcgenes of Harvey and Kirsten sarcoma virusesoriginate from divergent members of a family of normal vetebrate genes, Nature (London), 292,506, 1981. 153. Ellis, R. W., Stockert, E., and Fleissner, E., Association of endogenous retroviruses with radiationinduced leukemias of BALB/c mice, J. V#oI., 33, 6~2, 1980. I54. Erikson, E., CoOeR, M. S., and Erikson, R. L., In vitro synthesis of a functional avian sarcoma virus transforming-gone product, Nature (London), 274, 919, 1978. 155. Erikson, E. and Erikson, R. L., Isolation of amino acid acceptor RNA from purified avizn myeloblastosis virus, J. Mol. Biol., 52, 387, 1970. 156. Erikson, E. and Effkson, R. L., Association of 4S ribonucleic acid with oocornavirus nucleic acids, J. ViroL, 8,254, 1971. 157. Eva, A., Robbins, K. C., Andersen, P. R., Srinivasan, A., Tronick, S. R., Ruddy, E. P., Ellmore, N, W., Galen, A. "L, Lau~enberger, ,~. A., Papus, T. S., WestLn, E. B., Wong-St~, F., Oe31o,R. C., and Aaronson, S. A., Cellular genes analogous to tetroviral oncgenes are transcribed in human turnout cells, Nature (London), 295, 116, 1982. 158. Evans, L. H. and Cloyd, M. W., Generation of mink cell focus-forming v~,uses by Friend routine leukemia virus: recombinant with specific endogenous proviral sequences, 3. Viral., 49, 772, 1984. L59. Evans, L. H., Dresler, S., and Kabat, D., S~nthesis and gI~cosy|ation of pol:yprotein pr~rsors to the internal core proteins of Friend marine leukemia virus, J, Viral, 24, 865, 1977. 160. Evans, L. H., Duesberg, P. H., Troxler, D. H., and Scolnick, E. M., Spleen focus-forming Friend virus: identification of genomic RNA and its relationship to helper virus RNA, J. Viral., 31, 133, 1979. 161. Evans, L, H., Nunn, M., Duesberg, P. H., Tmx|er, D., and Scolnick, E. M., RNAs of defective and nondefective components of Friend anemia and polycythemia virus strains identified and compared, Cold Spring Harbor Syrup. QuaJ~t. Biol., 44, 823, 1979. 162. Fagg, B., Vthmeyer, K., Osiert~g, W., inulin, C., and Klein, B., Modified eryti~ropoiesis in mice infected with anemia or polycythemia-producin8 strains of Friend virus or with myeioproliferative virus, in In Vivo lnd In Vitro Erythropoiesis: The Friend System, Roast, G. B., Ed., Elsevier, Amsterdam, 1980, 163. 163. Failer, D. V. and Hopkins, N., 'rl oligonucleotide maps of Moloney and HIX routine leukemia viruses, Virolo~, 90, 265, t978. 164. Failer, D. V. and Hopkins, N., TI oligonucleofide maps of N-, B-, and B---NB.tropic muzine Leukemia viruses derived from BALB/c, J. Virot,, 26,143,197g. 165. Failer, D. V. and Hopkins, N.; TI oli|onucleotides that segrepte with tropism and with properties of gpT0 in recombinants between N- and B-tropic marine leukemia viruses, Y. Virol., 26, 153, 1978. 166. Failer, D, V., gommelaete, J., and Hopkins, N., Large Tl oligonucleotid~s of Molon~ leukemia virus missing in an erie guns recombinant, HIX, are. pt,e~nt on an int~tcdlular 21S Moloney vitae R N A apecies. Peor Natl. A ~ d . 5r U.S,A., 7~, 2964, 1978.

300

C R C Critical Reviews in O n c o l o g y / H e m a t o l o g y

167. Famulari, N. G., Buchhugen, D. L., Kleuk, FI.-D, and Flelssncr, E., Presence of murine leukemla virus envelope proteins gp70 and pl 5(E) in a common polyprotein of infected cells, J. ViroL, 20, 501, 1976, 1Og. Famulari, N. G,, Koohne, C, F., and O'Doand[, P, V., Leukemogeuesis by G~oss passage A murine leukemia virus: expression of viruses wizll recombinant envgenes in transformed cells, Proc. Natl, Acad. Sci. U.S,A., 79, 3872, 1982. 169. Fan, H,, RNA metabolism of murine leukemia virus: size analysls of nuclear pulse-labeled vlrusspecific RNA, Cell, 11,297, 1977. 170, Fan, H. and Baltimore, D., RNA metabollsm of marine leukemia virus: detection of virus-specific RNA sequences in infected and uninfected cells and identification of virus-specific messenger RNA, J. Mot, Biol., 80, 93, 1973. I71, Fan, H. and Besmer, P., RNA metabolism of routine leukemia virus. IL Endogenous vlrus-specific R N A in the uninfected BALB/c cell line JLS-Vg, J, Virol., 15, 836, 1975. 172. Fan, H. and Mueller-Lantzsch, N., RNA metabolism of murlne leukemia virus, Ill. Identification and quantitatJon of endogenous virus-speclfic mRNA in the uninfected BALB/c cell line JLS-V9, J. Virol, 18, 401, 1976. 173. Fan, H. and Verma, I, M., Size analysis and relationship of routine leukemia vlrus-specific mRNA's: evidence for transposition of sequences during synthesis and processing of subgenomlc mENA, J. ViroL, 26, 468, 1978. 174. Fanshier, L., Garapin, A.-C., McDonnell, J., Focus, A,, Levinson, W,, and Bishop, J, M., Deoxyribonucleic acid polymerase associated with avian tumor viruses: secondary structure of the deoxyribonucleic acid product, J. Virol., 7, 77, 1971. 175. Faras, A. Z, Dahiberg, J. E., Sawyer, R. C., Harada, F., Taylor, J. M., Levinson, W, E., Bishop, J. M,, and Goodman, H. M., Transcription of DNA from the 70S RNA of Rous sarcoma vires. II. Structure of a 48 RNA primer, J. Virol., 13, 1134, 1974, 176. Faras, A. J. and Dibble, N. A., RNA-dirccted DNA synthesis by the DNA polymerase of Rues sarcoma virus: structural and functional identification of 4S primer RNA in uninfected cells, Proc. Natl. Acad. Sci. U.S.A., 72, 859, 1975. 177. Faras, A. J., Garapin, A. C., Levin~on, W. E., Bishop, J. M,, and Goodman, H. M., The charactgrizz,tion of low-molecular-weight RNAs associated with 70S RNA of Rous sarcoma virus, J. ViroL, 12,334, 1973. 178. Faras, A, J., Taylor, J. M., Levlnson, W. E., Goodman, H. M,, and Bishop, J. M., RNA-dlrected DNA polymerase of Rous sarcoma vlrus: initiatieu of synthesis with 70S viral RNA as lemplate, J. Mof. Biol., 79, 163, 1973. 179. Fiore-Donnti, L. and Chleeu-Bianchi, L., Influence of host factors on development and type of leukemia induced in mice by Graffi virus, J. Natl. Cancer Inst., 32, 1083,1964. 180. Fiore-Donati, L., Chieco.Bianchi, L., Trldeute, G,, and PeuneUi, N., Studies on thymus-dependent mechanisms of mouse leukemogeuesis by Graffi virus, Natl. Cancer lost. MoanEr., 22, 587, 1966. Igl. Fischinger, P. L, Dunlop, N. M., and Blevins, C. S., Identification of virus found in mouse lymphomas induced by HIX routine oni:oranvirus, J. Virol,, 26, 532, 1978. 182. Fischinger, P. J., Frankel, A. E., Elder, J. H., Lecher, R. A., lhle, J. N., and Bologaesi, D. P,, Biological immunological, and biochemical evidence that HIX virus is a recombinant between Mo. Ioney'leukemia virus and a routine xenotropir C type virus, Virology, 90, 241,1978. 183. Fischinger, P. J., Nomura, S., and Bolognesi, D. P., A novel murine oncornavlrus with dual ecoand xenotropic properties, Proc. Natl. Acad. Sci. U.S.A., 72, 5150,1975. 184. Flugel,R. M. and Wells, R. D., Nucleotidesat the R N A - D N A covaleutbonds formed in the endogenous reaction by the avian myeloblastosis virus DNA polymerase, Virology, 48, 394, 1972. 185. Forchbammet, 1., Nexo, B. A., and Vanghan, M. H,, .It., Cellular pools of viral proteins in 3T3 cells chronically infected with Moloney routine leukemia virus, Virology, 71,134, 1976. 186. Franchini, O., Even, J., SF:rr, C. J., and Wong.Staal, F., oncsequeuces (v.fes) of Snyder-Theilen feline sarcoma virus are derived from noncontiguous regions of a cat celular geae (c-lea), Nature (Loodon), 290,154, 1981. 187. Frankel, A. E. and Fischinger, P, J., Nacleotide scquances in mouse DNA and RNA specific for Moloney sarcoma virus, Proc. Natl. Acad. Sci. U.S.A.,73, 3705, 1976. 188. Frankel, A. E. and Fischinger, P..I., Rate of divergence of cellular sequences homologous to segments of Moloney sarcoma virus, J. Virol., 21,153,1977. 189. Frankel, A. E., Gilbert, J. H., Porzi8, K. J., Scolnick, E. M., and Aaconson, S. A., Nature and distribution of feline sarcoma virus nucleotide sequences, J. Virol., $0, 821, 1979. 190. Friedrleb, R., Knngo H.-J., Baker, B., Vamlus, H. E., Goodman, H. M., and Bishop, J. M., Characterization of DNA complementary to nucleotide sequences at the 5'-terminus of the avian sarcoma virus genuine, Virology, 79, 198, 1977. 191. Friend, C., Cell- free transmission in adult Swiss mice of a disease having the character of a leukemia, J. Exp. Mecl., 105, 307~ 1957.

V o l u m e 5, Issue 3

301

192. Friend, C. and Haddad, J. R., Tumor formation with transplants of spleen or Iiver from mice with virus-induced leukemia, J. Natl. Cancer lnst.,25,1279, 1960. 193. Fritsch, E. and Temin, H. M., Formation and structure of infectious DNA of spleen necrosis virus, J. Virol., 21, 119, 1977. 194. Fujinaga, K., Parsons, J. T., Beard, J. W,, Beard, D,, and Green, M., Mechanism of carcinogenesis by RNA tumor viruses. III. Formation of RNA'DNA complex and duplex DNA molecules by the DNA polymcrase(s) of avian rnyeloblastosi~ virus, Prec. Natl. Acad. SoL U.S.A., 67, 1432, 1970. :195. Furuichi, Y., Shatkin, A. J., Stavnezer, E., and Bishop, J. M,, Blocked, methylated 5'-t~rminal sequence in avian sarcoma virus RNA, Nature (Leaden), 2~7, 618, t975. 196. Garapin, A..C., McDonnell, J. P., Levinson, W., Quintrell, N.) Fanshier, L., and Bishop, J. M,, Deoxyribonucleic acid polymerase associated with Rous sarcoma virus and avian myeloblastosis virus: properties of the enzyme and its product, J. Virol., 6, 589,1970. 197. Gardner, M. B., Type C viruses of wild mice: characterization and natural history of amphotropic, ecotropic, and xenotropic MuLV, Curt, Top. MJcrobiol. lramunol., 79, ;!15, 1978. 198. Gardner, M. B., Estes, J. D., Casagrande, J., and Rasheed, S,, Prevention of paralysis and suppression of lymphoma in wild mice by passive immunization to congenitally transmitted routine leukemia virus, J, Nat/., Cancer lnst.,64, 359, 1980, 199. Gab'doer, M, B., Henderson, B. E.. Ester, J. D., Rongcy, R. W,, C~agrande, 1., Pike, M., and H~eb~er, R, J., The e#demiology and virology of C-type virus-associated hematological cancer~ and related diseases in wild mice, Cancer Res., 36, 574, 1976. 200. Gardner, M. B., Klement, V., Rongey, R. W., McConahey, P., Estes, J. D., and Huebner, R, J., Type C virus expression in lymphoma-paralysis-prone wild mice, J. Natl. Cancer lost., 57,585,1976. 201. Gardner, W. U., Dougherty, T. F., and Williams, W. L., Lymphoid tumors in mice receiving steroid hormones, Cancer Res., 4, 73, 1944. 202. Gautsch, .I.W., Elder, J, H., Schindler, J., Jensen, F, C., and Lemur, R, A., Structural markers on core protein p30 of murine leukemia virus: functional correlation with Fv.l tropism, Prec. Natl. Acad. Sci. U.S.A., 75, 4170,1978. 203. Gelb, L. D., Mitstien, J. B., Martin, M, A., and Aaronson, S. A., Characterization of murine leukaemia virus-specific DNA present in ac,rmal taouse ceils, Nat. (London) N. Biol.) 244, 76, 1973. 204, Oelmann, E, P., Decleve, A., and K~plan, }t. S., Biological and biochemical differences among ecotropic C-type RNA ,,iral isolates chemically induced from C57BL/Ka meuse embryo cells M vitro, Virology, 85, 198, 1978, 205. Gerard, G. F. and Orandgenett, D. P., Purification and characterization of the DNA potymerase and RNase H activities in Moloney routine sarcoma.leukemia virus, J. ViroL, 15, 785, 19"/5. 206. Ghysdael, J., Hubert, E., Trlvn~ek, M., Bolognesi, D, P., Burney, A,, Cieuter, Y., Huez, G., Kettmann, R,, Marbaix, G., Portetelie, D., and Chantrenne, H., Frog oocyte~ synthesize and completely process the precursor polypeptide to viriott structural proteins after micro~n]ection of avian myelobiastosis virus RNA, Prec. Natl. Acad. Sci. U.S.A., 74, 3230, /977. 207. Gianni, A. M., Smotkin, B., and Weinberg, R. A., Murine leukemia v~rus: detection of unintegrated double-stranded DNA forms of the provirus, Prec. Natl. Acad. gel U.S.A., 72, 447, 1975. 208. Gielkens, A. L. J., Salden, M. H. L., and Bloemendal, H., Virus-specific messenger RNA on free and membrane.bound polyribosomes from ceils infected with Rauscher leukemia virus, Prec. Natl. Acad. ScL U.S.A., 71, 1093, 1974. 209. Gielkens, A. L. J., Van Zaane, D., Bloemer~, H. P. J., and Bloemendal, H., Synthesis of Rauscher murine leukemia virus-specific polypeptides in vitro, Proc. Natl. Acad. Sci. U.S.A., 73,356, 1976. 210. Gilboa, E., Golf, S., Shields, A,, Yoshimur~t, F., Mitra, S., and Baltimore, D., In vitro synthesis of a 9-kbp terminally redundant DNA carrying the infectivity of Moloney murine leukemia virus, Ceil, 16, 863,1979. 211. GiBes#e, D,, Marshall, S., and Guild, R. C., RNA of RNA turnout viruses contains poly A~ Nat. (London) hl. Biol., 236, 227, 1972. 212. Gilmcr, T. M. and Parsons, J. T., Analysis of cellular integration sites in avian sarcoma virus-infected duck embryo cells, J. Virol., 32, 762, 1979. 213. Godard, C., Robin, J., and Boiron, M., Effects of actinomycin D on early steps of replication in vitroof murine sarcoma virus (Moloney), J. Gun. Virol., 22, 293,197r 214. Goff, S. P., Gilboa, E., WiRe, O. N., and Baltimore, D., Structut'e of the Abelson routine leukemia virus genuine and the homologous cellular gent: studies with cloned viral DNA, Cell, 22, 777, 1980. 215. Goff, S. P., WiRe, O. N., Oilboa, E., Rosenberg, N,, and Baltimore, D., Genuine structure of Abelson murine leukemia virus variants: proviruses in fibroblasts and lymphoid cells, J. Virol., 38, 460, 198t. 21~. Goldfarb, M. P. and Weinberg, R. A., Physical map of biologically active Harvey sarcoma virus unintegrated linear DNA, J. ViroL, 32, 30, 1979. 217. Golomb, M. and Grandgenett, D, P,, Endonuclcase activity of purified RNA~direct~ DNA polymerase from avian myeioblastosis virus, J. Biol. Chent., 254,1606, 1979.

302

C R C Critical R e v i e w s in O n t o l o g y ~ H e m a t o l o g y

218, Gonda, M, A,, Kaminchlk, J., Oliff,A,, Menke, J., Nagashima, K,, and Scolnick, E. M., Heteroduplex analysis of molecular clones of the pathogenic Friend virus complex: Friend murine leukemia virus, Friend mink cell focus-forming virus, and the polycythemia- and anemia-inducing strains of Friend spleen focus-forming virus, J. Virol., 51,306, 1984. 219. Graffi, A., Chlorolaukemia of mice, Ann. N. Y. Acad. $ci., 68, 540, 1957. 220. Graffi, A., Fay, F., and Schrnmm, T., Experiments on the hematological diversification of viral mouse leukemias, Natl. Cttncer Inst. Monogr., 22, 21, 1966. 221. Graft'i, A., Schramm, T., Bender, E., Gruffi, I., Horn, K. H., and Bierwolf, D., Cell free transmissible leukosis in syrian hamster, probably of viral aetiology, Br. J. Cancer, 22, 577, 1968. 222. Grandgenett, D. P., Gerard, G. F., and Green, M., Ribonuclease H: a ubiquitous activity in virious of ribonuclaic acid tumor viruses, J. Virol., 10, 1136, 1972. 223. Grandgenett, D. P., Golomb, M., and Vorn, A. C., Activation of an MgZ'-dependent DNA endonuclease of avian myeloblastosls virus a~J DNA polymarase by in vitro proteoiytic cleavage, J. Virol., 33,264, 1980. 224. Grandgenett, D. P., Vora, A. C., and Schiff, R. D., A 32,000-dalton nucleic acid-binding protein from avian retrovirus cores possesses DNA endonuciease activity, Virology, 89, 119, 1978. 225. Green, M. and Cartas, M., The genuine of RNA tumor viruses contains polyadenyiic acid sequences, Prec. Natl. Acad. Sci. U.S.A., 69, 791, 1972. 226. Green, M., Grandgenett, D., Gerard, G., Rho, H. M., Lonl, M. C., Robin, M., Salzburg, S., Shanmugam, G., Bhaduri, S., and Vecchio, G., Properties of oncornavirus RNA-directed DNA polymerase, the RNA template, and the intracellular products formed early during infection and cell transformation, Cold Spring Harbor Syrup. Quant. Biol., 39, 975, 1974. 227. Green, N., Hiai, H., Elder, J. H., Schwartz, R. S., Khiroya, R. H., Thomas, C. Y., Tsichiis, P. N., and Coffin, J. M., Expression of leukemogenic recombinant viruses associated with a recessive gene in HRS/J mice, J. Exp. Mad., 152, 249, 1980. 228. Gross, L., "Spontaneous" leukemia developing in C3H mice following inoculation, in infancy, with AK-leukemic extracts, or AK.embryos, Prec. Soc. Exp. Biol. Mad., 76, 27, 1951. 229. Gross, L., Pathogenic properties, and "vertical" transmission of the mouse leukemia agent, Prec. Soc. Exp. Biol. Mad.,78, 342, 1951. 230. Gross, L., Development and serial cell-free pas~agc of a highly potent strain of mouse leukemia virus, Prec. Soc. E~p. Biol. Mad., 94, 767, 1957. 231. Gross, L., Attempt to recover filterable agent from X-ray-induced leukemia, Aura Haematol., 19, 353, 1958. 232. Gross, L., Serial cell-free passage of a radiation-activated mouse leukemia agent, Prec. Soc. Exp. Biol. Mad., 100, 102, 1959. 233. Gross, L., Development of myeloid (chloro-)leukemia in thymectomized C3H mice following inoculation of lymphatic leukemia virus, Prec. $oc. Exp. Biol. Mad., 103,509, 1960. 234. Gross, L., Oncogenir Viruses, 3rd ed., Pergamon Press, Oxford, 1983. 235. Gross, L., Roswit, B., Mada, E. R., Dreyfuss, Y., and Moore, L. A., Studies on radiatlon-induced leukemia in mice, Cancer Bus., 19, 316, 1959. 236. Guntaka, R. V., Mahy, B. W. J., Bishop, J. M., and Varmus, H. E., Ethldium bromide inhibits appearance of closed circular viral DNA and integration of virus-specific DNA in duck cells infected by avian sarcoma virus, Nature (London), 253, 507, 1975. 237. Guntaka, R. V., Richards, O. C., Shank, P. R., Knng, H.-J., Davidson, N., Fritsch, E., Bishop, J. M., and Varrnus, H. E., Covalentiy closed circular DNA of avian sarcoma virus: purification from nuclei of infected quail tumor ceils and measurement by electz'on microscopy and gel electrophoresis, J. Mol. Biol., 106, 337, 1976. 238. Haas, M., Leukemogenic activity of thymotropic, ecotropie, and xenotropic radiation leukemia virus isolates, J. ViroL, 25, 705, 1978. 239. Haas, M., Sher, T., and Smolinsky, S., Leukemogenesis in vitroinduced by thymic epithelium reticulum ceils transmitting routine leukemia viruses, Cancer Res., 37, 1800. 1977. 240. Hackett, P. B., Swanstrom, R., Varmus, H. E., and Bishop, J. M., The leader sequence of the subgenomic mRNA's of Rous sarcoma virus is approximately 390 nucleotldes, J. ViroL, 41,527, 1982. 241. Hag~r, G. L., Chang, E. H., Chart, H. W., Garon, C. F., Israel, M. A., Martin, M, A., Seolnick, E. M., and Lowy, D. R., Molecular cloning of the Harvey sarcoma virus closed circular DNA intermediates: initial structural and biological characterization. J. ViroL, 31,795, 1979. 242. Hager. (3. L. and Donehowat, L. A., Observations on the DNA sequence of the extended terminal redundancy and adjacent host sequences for integrated mouse mammary tlunot virus, ICN.UCLA Syrup. Mol. Cell. Biol,, 18, 255, 1980, 243. Hankins, W. D., Kost, T. A., Koury, M. J., and Krantz, S. B., Erythroid bursts produced by Friend leukaemia virus/n vitro, Nature (London), 276, 506, 1978.

V o l u m e 5, Issue 3

303

244. Hankins, W. D. and Troxler, D., Erythroid bursts following in vitro infection of bone marrow cells with the anemia-inducing strains of Friend and Rauscher leukemia viruses, in In Vivo and In Vitro Erythropoiesis: The Friend System, Rossl, G. B., Ed., Elsevier, Amsterdam, 1980, 151. 245. Hnrada, F., Peters, G. G., and Dahlberg, J. E., The primer tI~NA for Moloney marine leukemia virus DNA synthesis. Nucleotide sequence and aminoacylation of tRNA w, J. Biol. Chem., 254, 10979, 1979. 246. Hat tley, J. W. and Rowe, W. P., Production of altered cell foci in tissue culture by defective Moloney sarcoma virus particles, Proc. Natl. Acad. Sci. U.S.A., 55,780, 1966. 247. Hartley, J. W. and Rowe, W. P., Naturally occurring routine leukemia viruses in wild mice: characterization of a new "amphotropic" class, J. Virol., 19, 19, 1976, 248. Hartley, J. W., Rowe, W. P., Capps, W. I., and Huebner, R. J., Isolation of naturally occurring viruses of the murine leukemia virus group in tissue culture, J. Virol., 3,126, 1969. 249. Hartley, J. W., Rowe, W. P., and Huebner, R. J., Host-range restrictions of murine leukemia viruses in mouse embryo cell cultures, J. Virof., 5,221, 1970. 250. Hartley, J. W., Wolford, N. K., Old, L. J., and Rowe, W. P., A new class of murine leukemia virus associated with deve[opment of spontaneous lymphomas, Proc. Natl. Acad. Sei. U.S.A,, 74, 789, 1977. 251. Haseltine, W. A. and Kleid, D. G., A method for classification of 5' termini of retroviruses, Nature (London), 273, 358, 1978. 252. Haseltine, W. A., Maxam, A. M., and Gilbert, W., Rous sarcoma virus genome is terminally redundant: the 5' sequence, Proe. Nail. Aeacl. Sci. U.S.A,,74, 989, 1977. 253. Hasthorpe, S. and Bol, S., Erythropoietin responses and physical characterization of erythtoid progenitor cells in Rauscher virus infected BALB/c mice, J, Cell Physiol., 100, 77, 1979. 254. Hays, E. F. and Vredevoe, D. L., A discrepancy in XC and oncogenicity assays for routine leukemia virus in AKR mice, CancerRes., 37,726, 1977. 255. Hayward, W. S., Size and genetic content of viral RNAs in avian oncovirus-infected cells, J'. Virol., 24, 47, 1977. 256. Hayward, W. S., Neel, B. G., and Astrin, S. M., Activation of a cellular one gene by promoter insertion in ALV-induced lymphoid leukosis, Nature (London), 290, 475, 1981. 257. Heard, J. M., Fichelson, S., Sola, B., Martial, M. A., Burger, R., Varet, B., and Levy, J. P., Malignant myeloblastic transformation of murlne long-term bone marrow cultures by F-MuLV: in vitro reproduction of a long-term leukemogenesis, and investigation of preleukemic events, Int. J. Cancer, 32, 237, 1983. 258. Heard, J. M., Fichelsoa, S., Sola, B., Martial, M. A., Varet, B., and Levy, J. P., Multistep virusinduced leukemogenesis in vitro: description of a model specifying three steps within the myeloblastir malignant process, Mol. Cell. Biol.,4, 216, 1984. 259. Herr, W., Nucleotide sequence of AKV marine leukemia virus, J. Virol., 49, 471, 1984. 260. Hilkens, J., Colombatti, A., Strand, M., Nichols, E., Ruddle, F., and Hilgers, J., Identification of a mouse gene required for binding of Rauscher MuLV envelope gp70, Somat. Cell Genet., 5, 39, 1979. 261. Hill, M. and Hillova, J., Virus recovery in chicken cells treated with Rous sarcoma cell DNA, Nat. (London) N. BioL, 237, 35, 1972. 262. Hill, M. and Hillova, J., Recovery of the temperature.sensitive mutant of Rous sarcoma virus from chicken cells exposed to DNA extracted from hamster cells transformed by the mutant, Virology, 49, 309, 1972. 263. Hill, M., Hillova, J., Dantehev, D., Mariage, R., and Goubin, G., Infectious viral DNA in Rous sarcoma virus-transformed nonproducer and producer animal cells, Cold Spring Harbor Syrup. Quant. Bio1.,39, 1015, 1974. 264. Hillova, J., Dantchev, D., Mariage, R., Plichon, M.-P., and Hill, M., Sarcoma and transformationdefective viruses produced with infectious DNA(s) from Rous sarcoma virus (RSV)-transformed chicken cells, Virology, 62,197, 1974. 265. Hippenmeyer, P. J. and Orandgenett, D. P., Requirement of the avian retrovirus pp32 DNA binding protein domain for replication, Virology, 137, 358, 1984. 266. Hishinuma, F., DeBoan, P. J., Astrin, S., and Skalka, A. M., Nucleotide sequence of acceptor site and termini of integrated avian endogenous provirus ev-l: integration creates a 6 bp repeat of host DNA, Ce11,23, 155, 1981. 267. Holland, C. A., Hartley, J. W., Rowe, W. P., and Hopkins, N., At least four viral genes contribute to the leukemogenicity of routine r~trovirus MCF 247 in AKR mice, J. ViroL, 53, 158, 1995. 268. Holland, C. A., Wozney, J., Chatis0 P. A., Hopkins, N., and Hartley, J. W., Construction of recomhinants between molecular clones of murine retrovirus MCF 247 and Akv: determinant of an in vitro host range property that maps in the long terminal repeat, J. Virol., 53, 152, 1985. 269. Holland, C. A., Wozney, J., and Hopkins, N., Nueleotide sequence of the 8p70 gene of routine retrovirus MCF 247, J. Virol., 47, 413, 1983.

304

C R C Critical R e v i e w s in O n t o l o g y ~ H e m a t o l o g y

270, Hopkins, N., $chindler, J., and Hynes, R., Six NB.tropic murine leukemia viruses derived from a Btropic virus of BALB/c have altered p30, J. ViroL, 21,309, 1977. 271, Horoszewicz, J, S., Leong, S. S,, and Carter, W. A,, Friend leukemia: rapid development of erythrnpoietln.indcpendent hematopoietic precursors, J. Natl. Cancer Inst., 54, 265, 1975. 272. Hsu, T. W., Sabran, J. L., Mark, G. E., Guntaka, R. V., and Taylor, J. M., Analysis of unintegrated avian RNA tumor virus double-stranded DNA intermediates, J. ViroL, 28) 810, 1978. 273. Hu, S. S. F., Lai, M. M, C., and Vogt, P. K., Characterization of the envgene in avian oncoviruses by heteroduplex mapping, J, ViroL, 27,667, 1978. 274. Hughes, S. H , Mutschlcr, A., Bishop, J. M,, and Varmus, H. E., A gnus sarcoma virus provirus is flanked by short direct repeats of a cellutar DNA sequence present in only one copy prior to integration, Proc. Natl. Acad. Set. U.S.A., 78, 4299, 1981. 275. Hughes, S. H., Shank, P. R., Spector, D. H,, Kung, H,-J., Bishop, J. M., Varmus, H, E., Vogt, P. K., and Breitlnan, M. L,, Proviruses of avian sarcoma virus are terminally redundant, co-extensive with unintegrated linear DNA and integrated at many sites, Cell, 15, 1397, 1978. 276, Hughes, S, H,, Vogt, P. K., Stubblefield, E., Bishop, J. M., and Varmus, H. E., Integration of avian sarcoma virus DNA in chicken cells, Virology, 108, 208. 1981. 277. Hunter, T. and Sefton, B. M., Transforming gone prodm.t of Rous sarcoma virus phosphorylates tyrosine, Proc. Natl. Acad. Set, U.S.A., 77, 1311, 1980. 278. Hnrwitz, J. and Lois, J. P., RNA-dependent DNA polymerase activity of RNA tumor viruses. I. Directing influence of DNA in the reaction, J. Virol., 9, 116, 1972. 279. lhle, J, N., Keller, J., Oroszlan, S., Henderson, L. E., Copeland, T. D., Fitch, F., Prystowsky, M. IL, Goldwasser, E., Schrader, J. W., Palaszynski, E., Dy, M., and Lebei, B., Biologic properties of homogeneous interleukin 3. 1. Demonstration of WEHI-3 growth factor activity, mast cell growth factor activity, P cell-stimulating factor activity, colony-stimulating factor activity, and hlstamiPeproducing cell-stimulating factor activity, J. Immnnol., 131,282, J983. 280. lkeda, H., Hardy, W., Jr., Tress, E., and Fleissner, E., Chromatographic separation and antigenic analysis of proteins of the oncornaviruses. V. Identification of a new murine viral protein, pl 5(E), 3., Virol., 16, 53, 1975. 28I. Ikeda, H. and Odaka, T., Cellular expression of routine leukemia virus gp70-related antigen on thymocytes of uninfected mice correlates with Fv-4 gone-controlled resistance to Friend leukemia virus infection, Virology, 128,127,1983. 282. Ishimoto, A.) Adachi, A.) Sakai, K., Yorifuji, T., and Tsuruta, S., Rapid emergence of mink cell focus-forming (MCF) virus in various mice infected with NB-troplc Friend virus, Virology, 113,644, 1981, 283. Jacquet, M., Groner, Y., Monroy, G., and Hurwitz, J., The in vltrosynthesis of avian myeloblastosis viral RNA sequences, Proc. Natl. Acad. Sci. U.S.A., 71, 3045, 1974. 284. Jamjoom) G., Karshin, W. L., Naso. B., Arcement, L. J., and Arlinghaus, R. B., Proteins of Rauscher murine leukemia virus: resolution of a 70,000-dalton nonglycosylated poJypeptide containing p30 peptide sequences, Virology, 68, 135, 1975. 285. Jamjoom, G, A,, Naso, R. B., and Arlinghaus, R. B., Selective decrease in the rate of cleavage of an intracellular precursor to Rauscher leukemia virus p30 by treatment of infected cells with aetinomycln D, J. Virol., 19, 1054, 1976. 286. Jam~oom, G. A.) Naso, R. B. and Arlinghaus, R. B., Further characterization of intracellu]ar precursor polyproteins of Rauscher leukemia virus, Virology, 78. 11, 1977. 287. J'amjoom) G. A., Ng., V, L., end Arlinghaus, R. B., Inhibition of maturation of Rauscher leukemia virus by amino acid analogs, J. ViroL, 25,408, 1978. 288. Jenkins. N, A~. and Cooper, G, M., Integration, expression, and infectivity of exogenously acquired proviruses of gnus.associated virus-O, 3". Virol., 36, 684, 1980. 289. Jenkins, V. K. and Upton, A. C., Cell-free transmission of radiogenic myeloid leukemia in the mouse) Cancer Res., 23, 1748, 1963. 290. John, R. H., BlUnter, M. A., and Weissmann, C., Mapping of biological functions on RNA of avian tumor viruses: location of regions required for ~ransformation and determination of host range, Pror Natl. Acad. Sci. U.S.A.,72, 4772, 1975. 291. John, R. H., Billeter, M. A., and Weissmann, C., Concordance of the RNA termitfi of recombinants from crosses between avian retroviruses with different termini, Virology, 85,364, 1978. 292. Joklik, W, K. and Zwectlnk, H., The morphogenesis of animal viruses, Annu. Roy. Goner., 5,297) 1971. 293. Jolicocur, P. and Baltimore, D., Effect of Fv-I gone product on proviral DNA formation and integration in cells infected with murine leukemia viruses, Proc. Natl. Acnd. Sci. U.S.A., 73, 2236,1976. 294. Jolicoeur, P,, Nicolaiew, N., DesGroseillers, L., and Rassart, E., Molecular'~laning of infectious viral DNA from ecotropic neurotropic wild mouse retrovirns, J, Virol., 45, 1159, 1983. 295: Jolicocur, P; and R ~ u ' t , E., Effect of Fv-I gone product on synthesis of linear and supercoilcd viral DNA in cells infected With routine leukemia virus, s tirol., 33, 183, 1980.

V o l u m e 5, Issue 3

305

296, Jollcoear, P. and Rassart, E., Fate of unintegrated viral DNA in Fv.l permissive and resistant mouse cells infected with routine leukemia virus, ./. Viro]., 37, 609, 1981. 297, Ju, G,, Boone, L,, and Skalka, A. M., Isolation and characterization of recombinant DNA clones of avian retrnviruses: size heterogeneity and instability of the direct repeat, J. Virol., 33, 1026, 1980. 298. Ju, G. and Skalka, A. M., Nucleotide sequence analysis of the long terminal repeat (LTR) of avian retroviruses: structural similarities with transposable elements, Cell. 22, 379, 1980. 299. Junghans, R. P., Hu, S., Knight, C. A., and Davidsnn, N., Heterodupiex analysis of avian RNA tumor viruses, Prec. Natl. Acad. Sol. U.S.A., 74, 477, 1977. 300. Kal, K,, lkeda, H,, Yuasa, Y., Suzuki, S., and Odaka, T., Mouse strain resistant to N-, B-, and NBtropic murine leukemia viruses, J. Virol., 20, 436, 1976. 301. Kakefuda, T., Dingmnn, C. W., Bak, T. M., Hatanaka, M,, and Kitano, Y., Reverse transcription nf the viral genome associated with the plasma membrane after infection with RNA tumor viruses, Cancer Res., 34, 679, 1974. 302. Kaplan, H. S., Influence of thymcctomy, splenectomy, and gnnadectomy nn incidence of radiationinduced lymphoid tumors in strain C57 black mice, J. Natl. Canccrlnst., 1i, 83, 1959. 303. Kaplan, H. S., Brown, M. B., and Paull, J., Influence of pestlrradiation thymectomy and of thymic implants on lymphoid tumor incidence in C57BL mice, Cancer Res., 13,677, 1953. 304. Kapian, H. S., Carncs, W. H., Brown, M. B., and Hirsch, B. B,, Indirect induction of lymphomas in irradiated mice. I. Tumor incidence and morphology in mice hearing nonirradiated thymic grafts, Cancer Res., 16, 422, /956. 305. Karpas, A. and Milstcin, C., Recovery of the gcnome nf routine sarcoma virus (MSV) after infection nf ceils with nuclear DNA from MSV transformed non-virus producing cells, Eur. J. Cancer, 9, 295, 1973. 306. Karshin, W. L,, Arcement, L. J., Nasn, R. B., and Arlinghaus, R. B., Common precursor for Rauseher leukemia virus gp69/71, plS(E), and pl2(E), J. ViroL, 23,787, 1977. 307. Katz, R. A., Maniatis, T. M., and Guntaka, R. V,, Translation of avian sarcoma virus RNA in Xenopus laevlsoocytcs, BJochem. giophys. Reg. Commun., 86, M.7, 1979. 308. Kawashima, K.. Ikeda, H., Stockert, E., Takahashi, T., and Old, L. J., Age-related changes in cell surface antigens of preleukemlc AKR thymocytes, J. Exp. Mud., 144, 193, 1976. 309. Kelth, J. and Fraenkel-Conrat, H., Identification of the 5' end of Rous sarcoma virus RNA, Prec. Natl. Acad. Sci. U.S.A., 72, 3347, 1975. 310. Kelly, M., Holland, C. A., Lung, M. L., Chattopadhyay, S. K., Lowy, D. R., and Hopkins, H. H., Nucleotide sequence of the 3' end of MCF 247 murine leukemia virus, J. Virol., 45,291, 1983. 311. Kemp, M. C., Basak, S., and Compans, R, W., Glycopeptides of murine leukemia viruses. I. Comparison of two ecotropic viruses, J. Virol.,31, I, 1979. 312. Kemp, M. C., Famulari, N. G., O'Donnell, P. V., and Compans, R. W., Glycopeptldes of murine leukemia viruses. II. Comparison of xenotrnpic and dual-tropic viruses, J. Virol., 34, 154, 1980. 313. Kerr, L M., Olshuvsky, U., Lndish, H. F., and Baltimore, D., Translation of murlne leukemia virus RNA in cell-free systems from animal cells, J. Virol., 18, 627, 1976. 314. Keshet, E., O'Rear, J. J., and Temin, H, M., DNA of noninfectious and infectious integrated spleen necrosis virus (SNV) is r with unin~grated SNV DNA and not grossly abnormal, Cell, 16, 51. 1979. 315. Keshet, E. and Temin, H. M., Sites of integration of reticulocndothcliosis virus in chicken DNA, Prec. Natl. Acad, Sci. U.S.A., 75, 3372, 1978. 316. Khoury, A. T. and Hanafusa, H., Synthesis and integration of viral DNA in chicken cells at different times after infection with various multiplicities of avian oncornavirus, J. Virol., 18, 383. 1976. 317. King, A. M. Q.. High molecular weight RNAs from Rous sarcnma virus and~ Moloney murine leukemia virus contain two subunits, J. Biol. Chem., 251,141, 1976. 318. Knans, R. J., Hippenmeyer, P. J., Miara, T. K., Grnndgenett, D. P., Miillec, U. R., and Fitch, W. M., Avian retrovirus pp32 DNA bindln8 protein. Preferential binding to the promoter reginn of long terminal repeat DNA, Biochemlstry,23, 350, 1984. 319. Koch, W., Hunsmunn, G., and Friedrich, R., Nacleotlde sequence of the envelope gene of Friend murioc leukemia virus, Jr. Virol.,45, 1, 1983. 320. Koch, W., Zlmmermann, w., Oliff, A., and Frledrich, R,, Molecular analysis of the envelope gene and long terminal repeat of Friend mink cell focus-iuducin8 vires: implications for the functions of these sequences, J. Virol., 49, 828, 1984. 321. Kopchick, J. J., Harless, J., Geisser, B. S,, Kinam, R., Hewitt, R. R., and Ariinghaus, R. B,, Endodeoxyribnnuciease activity associated with Ruuscher murine leukemia virus, J. Virol., 37, 274, 1981. 322. Kopchick, J. 3,, .lamjoom, G, A., Watson, K. T., and Arlinghuus, R. B., Biosynthesis of reverse transcriptase from Rauscher murioc leukemia virus by synthesis, and clenvage of a &aB'-polreadthrnugh viral precursor polyprotein, Prec. Nat/. Acud. Sci. U.S.A., 75. 2016, 1978.

306

C R C Critical R e v / e w s in O n c o l o g y / H e m a t o l o g y

323. Kost, T, A., Koury, M. 3,, Hankins, W, D., and Krantz, S, B., Target cells for Friend virus-induced erythroid bursts, in vitro, Cell, 18, 145, 1979. 324. Krakower, J. M., Barbacid, M., and Aaronson, S. A., Radioimmunoassay for loammalian type C viral reverse transeriptase, J. Virol., 22, 331, 1977. 325. Krzyzek, R. A., Collett, M. S., Lau, A. F., Perdur M. L., Lois, J. P., and Faras, A. J., Evidence for splicing of avian sarcoma virus 5'-terminal genomie sequences onto viral-specific RNA in infected cells, Prec. Neff. Acad. Sci. U.S.A., 75, 1284, 1978. 326. Kryzyzek, R, A., Lau, A. F., Vogt, P, K., and Faras, A. J., Quantitation and localization of Rous sarcoma virus-specific RNA in transformed and revertaot field vole cells, J. Virol., 25, 518, 1978. 327. Kumar, V. and Bennett, M., Mechanisms of genetic resistance to Friend leukemia virus leukemia in mice. II. Resistance of mitogen.responsive lymphoeytes mediated by marrow-dependent ceils, ). Exp. Med., 144, 713, 1976. 328. Kunii, A., Takemoto, H., and Furth, J,, Leukemogenic filterable agent from estrogen-induced thymic lymphoma in RF mice, Prnc. Soc. Exp. Biol. Med., 119, 1211, 1965. 329. Lal, M. M. C. and Duesberg, P. H., Adeoylic acid-rich sequence in RNAs of Rnus sarcoma virus and Rausches mouse leukaemia virus, Nature (London), 235, 383, 1972. 330, Lai, M. M. C., Duesbesg, P. H., Horst, J., and Vogt, P. K., Avian tumor virus RNA: a comparison of three sarcoma viruses and their transformation-defective derivatives by oligonucleotide fingerprinting and DNA-RNA hybridization, Prec. Natl, Aead. Sci. U.S.A., 70, 2266, 1973. 331. Laimins, L. A., Gruss, P., Pozzatti, R., and Khoury, G., Characterization of enhancer elements in the long terminal repeat of Molooey murine sarcoma virus, J. Virol., 49, 183, 1984. 332. Land, H., Parada, L. F., and Weinbesg, R. A., Cellular oncogenes and muhistep carcinogenesis, Science, 222,771, 1983. 333. Land, H., Parada, L. F., and Weinberg, R. A., Tumorigenic conversion of primary embryo fibreblasts requires at least two cooperating oocogenes, Nature (London), 304, 596, 1983. 334. Landcli, ~. and Fox, C. F., Isolation of BPgp70, a fibrobiast receptor for the envelope antigen of Rauscher routine leukemia virus, Prec. Natl. Acad. Sei. U.S.A., 77, 4988, 1980. 335. Lange, J., Frank, H., Huosmaon, G., Moennig, V., Wollmano, R., and Sch~fer, W., Properties of mouse leukemia viruses. VL The core of Friend virus; isolation and characterization, Virology, 53, 457, 1973. 336. Law, L. W,, Effect of gonadectomy and adrenalectomy on the appearance and incidence of spontaneous lymphoid leukemia in C58 mice, J. Natl. Cancer Inst., 8, 157, 1947. 337. Law, L. W. and Miller, J. H., The influence of thymectomy on the incidence of carcinogen-induced leukemia in strain DBA mice, J. Natl. Cancer Inst., 11,425, 1950. 338. Leamnson, R. N., Shander, M. H. M., and Halpesn, M. $., A structural protein complex ifi Moloney leukemia virus, Virology, 76, 437, 1977. 339. Lr Bousse.Kecdiles, M, C., Smadja-Joffr F., Klein, B., cainou, B., and Jasmio, C., Study of a virus-induced myeloproliferative syndrome associated with tumor formation in mice, Eur. J. Cancer, 16, 43,1980. 340. Lebowitz, P., Oncogenic genes and their potential role in human malignancy, J. C?io, Once1., 1,657, 1983. 341. Ledbr J. A., Two-dimensional analysis of murine leukemia virus gag- gone polyproteins, Virology, 95, 85, 1979. 342. Ledbettec, J. A., Nowinski. R. C., and Eisenman, g. N., Biosynthesis and metabolism of viral proteins expressed on the surface of routine leukemia virus-lnfected cells, Virology, 91, 116, 1978. 343. Ledbetter, ,[. A., Nowinski, R. C., and Emery, S., Viral proteins expressed on the surface of murlne leukemia cells; J. ViroL, 22, 65, 1977. 344. Lee, J. S., Varmus, H. E., and Bishop, J. M., Virus-specific messenger RNAs in permissive cells infected by avian sarcoma virus, J. Biol. Chem., 245, 8015, 1979. 345. Lemay, G. and Jolicocur, P., Rearrangement of a DNA sequence homologous to a cell-virus junction fragment in several Moloney murine leukemia virus-induced rat thymomas, Prec. Natl. Acad. Sci. U.S.A.,81, 38. 1984. 346. Lenard, J. and Compans, R. W., The membrane structure of lipid-containing vesicles, Biuchim. Biophys, Acre, 344, 5 I, 1974. 347. Leoz, J., Celandec. D., Crowther, R. L., Patarca, R., Perkins, D. W., and Haseltine, W. A., Determination of the leukaemogenieity of a murior retrovi~s by sequences within the long terminal repeat, Nature (London), 30g, 467, 1984. 348. Long, J., Crowther, R., Klimenko, S., and Haseltioe, W., Molecular cloning of a highly leukemogenie, ecotropic retrovirus from an AKR mouse, J. Virol., 43,943, 1982. .~ 349. Lenz, J., Crowthec, R , Str~.r162 A., and Haseltine, W., Nucleotide sequence of the Akv eovgene, J. Virol.,42, 519, 1982. 350. Lonz, J. and HP~eltine, W. A., Localization of the leukemogenic determinants of SL3-3, and ecotropic, XC-positive murine leukemia virus of AKR mouse origin, J. ViroL, 47, 317, 1983.

V o l u m e 5, Issue 3

307

351. Leonard, A. and Deeleve, A., A chromosome marker for studies in the C57 black strain of mice, Leuk. Res.,3, 93, 1979. 352. Leong, J. A., Garapin, A.-C., Jackson, N., Fanshier, L., Levioson, W., and Bishop, J. M., ViTusspecific ribonucleic acid in cells producing Rous sarcoma virus: detection and characterization, J. Virol., 9, 891, 1972. 353. Leong, J. A., Levioson, W., and Bishop, J. M., Synchronization of Rous sarcoma virus production in chick embryo cells, Virology, 47, 133, 1972. 354. Leong, J. A., Levinson, W., Levy, J. A., Xenotropic viruses: routine leukemia viruses associated with NIH Swiss, NZB, and other mouse strains, Science, 182, 1151, 19'/3. 355. Levin, J. G., Grlmley, P. M,, Ramseur, J. M., and Becezesky, L K., Deficiency of 60 to 70S RNA in murlne leukemia virus particles assembled in cells treated with actinomycin D, J. Virol., 14, 132, 1974. 356. Levin, J. G. and Rosenak, M. J., Synthesis of murlne leukemia virus proteins associated with virions assembled in actinomycin D.treated ceils: evidence for the persistence of viral messenger RNA, Proc. Nat/. Aead. Sol. U.S.A., 73, 1154, 1976. 357. Levinson, B., Khoury, G., Vande Woude, G., and Gruss, P., Activation of SV40 genome by 72.base pair tandem repeats of Moloney sarcoma virus, Nature (London), 295,568, 1982. 358. Levy, J. A., Xenotropic viruses: murlne leukemia viruses associated with NIH Swiss, NZB, and other mouse strains, Science, 182, 1151, 1973. 359. Levy, J. A., Autoimmunity and neoplasia: the possible role of C-type viruses, Am. J. Clio. Pathol., 62, 258, 1974. 360. Levy, J. A., Host range of murine xcnotropic virus: replication in avian cells, Nature (London), 253, 140, 1975. 361. Levy, S. B., Blankstein, L. A., Vinton, E. C., and Chambers, T. J., Biologic and biochemical characteristics of Friend leukemic cells representing different stages of a malignant process, in Oncogenic Viruses and Host Cell Genes, lkawa, Y. and Odaka, T., Eds., Academic Press, New York, 1979, 409. 362. Liao, S.-K. and Axelrad, A. A., Erythrupoietin-independent erythroid colony formation in ~titro by hemopoictic cells of mice infected with Friend virus, Int. J. Cancer, 15,467, 1975. 363. Lieberman, M. and Kaplan, H. S., Leukemogenic activity of filtrates from radiation-lnduced lymphoid tumors of mice, Science, 130, 387, 1959. 364. Lilly, F., Susceptibility to two strains of Friend leukemia virus in mice, Science, 155,461, 1967. 365. Lilly, F., Fv-2: identification and location of a second gene governing the spleen focus response to Friend leukemia virus in mice, J. Natl. Cancerlnst.,45,163, 1970. 366. Lilly, F. and Pincus, T., Genetic control of murine viral leukemogenesis, Adv. Cancer Res., 17, 23 I, 1973. 367. Linemeyer, D. L., Menke, J,. G., R~seetti, S. K., Evans, L. N., and Scolnick, E: M., Envelope gene sequences which encode the gp52 protein of spleen focus-forming virus are required for the induction of erythroid,cell proliferation, J. Vi,ol., 43,223, 1982. 368. Linemeyer, D. L., Ruseetti, S. K., Menke, J. G., and Scolnick, E. M., Recovery of biologically active spleen fo~:us-formlng virus from molecularly cloned spleen focus-forming virus-pBR322 circular DNA by cotransfection with infectious type C retrovlral DNA, 3. Virol., 35,710, 1980. 369. Linemeyer, D. L., Ruscetti, S. K., Scolnick, E. M., Evans, L. H., and Duesber$, P. H., Biological activity of the spleen focus-forming virus is encoded by a molecularly cloned subgenomic fragment of spleen focus-forming virus DNA, Proc. Nat/. Acad. $r U.S.A., 7g, 1401, 1981. 370. Loni, M. C. and Green, M., Detection and localization of virus-specific DNA by in situhybridization of cells during infection and ~-apid transformation by the routine sarcoma-leukemia virus, Proc. Natl. Acad. ScL U.S.A., 71, 3418, 1974. 371. Lovingec, G. G. and Schochetman, G., 5'-terminal nueleotlde sequences of the Rauseher leukemia virus and gibbon ape leukemia virus genonles exhibit a high degree of correspondence, J. Virol., 32, 803, 1979. 372. Lovinger, G. G. and Schochetman, G., 5' terminal nucleotide sequences o~ type C retroviruses: features common to noncoding sequences of eocaryotic messenger RNAs, Ceil, 20, 441, 1980. 373. Lowy, D. R., Chattopadhyay, S. K., Teieh, N. M., Rowe, W. P., and Levine, A. S., AKR rout/he leukemia virus genome: frequency of sequences in DNA of high-, low-, and non-virus-yielding mouse strains, Proc. Natl. Acad. Sci. U.S.A., 71, 3555, 1974. 374. Lu, A. H., Soong, M. M., and Woog, P. K. Y., Maturation of Moloney murine leukemia virus, Virofc~!gy,93,269, 1979. 375. Lung, M. L., Hartley, J. W., Rowe, W. P., and Hopkins, N. H., Large RNase T~-resislant oligonudeotldes encoding pI5E and the U3 region of the long terminal repeat distinguish two biological classes of mink ceil focus-forming type C viruses of inbred mice, J. Viiol., 45,275, 1983. 376. MacDonald, M. E., Johnson, G. R., and Bernstein, A., Different pseudotypes of Friend spleen focusforming virus induce polycythemia and erythropoietin-indeperident colony formation in serum.free medium, Virology, I IO, 231, 1981.

308

C R C Critical Reviews in O n c o l o g y / H e m a t o l o g y

377. MacDonald, M, E., Mak, T. W., and Beznstcin, A,, Erythrolcukemia induction by replication-competent type C virusescloned from the anemia- and polycythemia.inducing isolatesof Friend leukemia virus, J" Exp. Med., IS J, 1493, I980. 378. MacDonatd,,M. E., Reynolds, F. H., Jr., Van de Van, W. J. M., Stephenson, J. g., Mak, T. W., and Bernstein, A., Anemia- and polycythemia-inducing isolates of Friend spleen focus-forming virus. Biological and molecular evidence for two distinct viral genomes, J. Exp, Mad,, 151,1477,1980. 379, Mager, D., MacDonald, M. E., Robson, I. B., Mak, T. W., and Bernstein, A., Clonal analysis of the late stages of erythroleukemia induced by two distinct strains of Friend leukemia virus, Mo]. Cell. BioL, 1,721,198i. 380. Moper, D., Mak, T. W., a~.d Bernstein, A., Friend leukemia virus-transformed cells, unlike normal stern cells, lotto spleen colonies in SI/SP mice, Nature (London), 288, 592, 1980. J8l. Mager, D., Mak, T. W., ar~ BernsIein, A., Quantitative colony method for tumorigenic cells transformed by two distinct strains of Friend leukemia virus, Prec. Natl. Acad. $ci. U.S.A., 78, I703, 1981. 382. Maisel, J., Klernet, V., Lai, M, M.-C., Ostertag, W., and Duesbcrg, P., Ribonucleic acid components of,murine sarcoma and leukemia viruses, Prec. Nail. Acad. Sci. U.S.A., ?0, 3536,1973. 383. Majors, J. E. and Varmus, H. E., Nucleotide sequences at host-proviral junctions for mouse mammary tum~ur virus, Nature (Lopdon), 289,253, 1981, 384. Mak, T. W., Axelrad, A. A., and Bernstein, A., Fv.2 locus controls expression of Friend spleen focus-forming virus-specific sequences in normal and infected mice, Prec. Null. Acad. 3ci. U.S.A., 76, 5809, 1979. 385. Mak, T. W,-, Gambit, C. L., MacDonald, M. E., and Bernstein, A,, Host control of sequences specific to Frieml erythroleuken~a virus in norma! and leukemic mice, Cold Spring Harbor Syrup. Quant. Biol.,44, 893,1979. 386. Mak, T. W., Penrose, D., Gamble, C., and Bernstein, A., The Friend spleen focus-forming virus (SFFV) genuine: fractionation and analysis of SFFV and helper virus.related sequences, Virology, 87, 73, 1978. 387. Manly, K. F., Stonier, D. F., Bromfield, E., and Baltimore, D., Forms of deoxyribonucleic acid produced by v~[rionsof the ribonucleic acid tumor viruses, J. ViroL, 7,106, 1971. 388. Manteuil.Brutlag, S., Liu, S., and Kaplan, H, S., Radiation leukemia virus contains two distinct viral RNAs, Cell, i9, 643, 1980. 389. Marcelletti, J. and Furmanski, P,, Spontaneous regression of Friend virus-induced erythroleukemia. IiI. The role of maeropl~ages in regression, J. lmmunol., 120, 1, 1978. 390. Marcelletti, J. and Furmanski, P., Infection of macrophages with Friend virus: relationship to the spontaneous regression of viial erythroleukemia, Cell, 16,649, 1979. 391. Markham, P. D. and Baluda, M. A., Integrated state of oncornavirus DNA in normal chicken cells and i~ ceils tranformed by avian myeloblastosis virus, J. Virol,, 12, 721, 1973, 392. Marks, P. A. and Rifkind, R. A., Erythroleukemic differentiation, Annu. Rer Biochem., 47,419, 1978. 393. Marshall, T. H. and Rapp, U. g., Genes controlling receptors for ecotropie and xenotropic type C virus in Mus cervicolorand Mus musculus, J. ViroL,29, 501, 1979. 394. Martin, H. L,, Salden, M., and Bloemendal, H., Translation of avian myeloblastosis virus RNA in a reticulocyte cell-free system, Biochcm. Biophys. Res. Commun., 68, 249, 1976. 39L McCarter, J. A., Bali, J. K., and Fret, J. V., Lower limb paralysis induced in mice by a temperaturesensitive mutant of Moloney leukemia virus, 2, Nat2, Cancer last., 59, 179,1977. 396. McCool, D., Mak, T. W., and Bernstein, A., Cellular regulation in Friend virus induced erythroleukemia. Studies with anemic mice of genotype Sl/S?, J. f:~p. Mad,, 149, 837, 1979. 397. McDonnell, J. P., Garapin, A.-C,, Levinson, W. E., Quintrell, N., Fanshier, L., and Bishop, J. M., DNA polymerases of Rous sarcoma virus: delineation of two reactions with actinomycin, Nature (London), 228, 433, 1970. 398. McEndy, D. P., Boon, M. C., and Furth, J., On the role of thymus, spleen, and gonads in the development of leukemia in a high-leukemia stock of mice, Cancer Res., 4, 377, 194,4. 399. McGarry, M. P., Sleeves, R. A., Eckner, R. J,) Mirand, E. A., and T~del, P. J., Isolation of a myelogenous leukemia-inducing virus from mice infected with the Friend virus complex, Int. Z Canccr, J3,867, 1974. 400. McGinnis, J., Hizi, A., Smith R. E., and Leis, J. P., In vitro translation of a 180,000-dalton Rous sarcoma virus precursor polypeptide containing both the DNA polymerasr and the group-specific antigens, Virology, 84, 518,1978. 401. McGrath, M, S~, Declare, A., Lieberman, M., gal~lan, H. S,, and Weissma,., i. L., Specificity of cell surface virus receptors on radiation leukemia virus and radiation-induced thym'c lymphomas, J'. Virol., 28,819,1978. 402. McGrath, M. S. and Weis)man, I. L., AKR leukemogenesis: identification and biological significance of thymic lympttoma receptors for AKR retroviruscs; Cell, 17, 65. 1979.

' V o l u m e 5, i s s u e 3

309

403. Mellon, P. and Duesberg, P. H., Subgenomic, cellular Rous ~arcoma virus RNAs contain oligonur from.the 3' half and the 5' terminus of virion RNA, Nature (London), 270,631, 1977. 404. Metcalf, D., Moore, M. A. S., and Warner, N. L., Colony formation in vitro by myelomonocytic leukemic celIs, J, Natl. Cancer l~st., 43,983, 1959. 405. Mirand, E. A., Virus-induced erythropoicsis in bypertransfused-polyCythemic mice, Science, 156, 832,1967. 406. Mirand, E. A., Prentice, +. C., Hoffmann, J. G., and Grace, I. T., Jr., Effect of Friend virus in Swiss and DBA/I mice on Fe ~9uptake, Proc. $oc~ Exp. Biol. Mud., 106, 423, 1961. 407. Mirang[, E. A., Sleeves, R. A., AviIa, L., and Grace, .L T., Jr., Sp|een fo=us formation by poiycythemic strains of Friend leukemia virus, Proc. Sor E~p. BioL Med., 127, 900,1968. 408. Mirand, E, A,, Steeves, R. A., Lange, R. D., and Grace, J, T,, Jr., Virus-induced polycythemia in mice: erythropoicsis without erythropoie~in, Proc, $oc. Exp. Biol. Mud., 128, 844, 1968. 409. Misra, T. K., Grandgenett, D. P., and Parsons, J. T., Aviafi rewovir'tJs pp32 DNA.binding protein. I. Recognition or specific sequences on retrovirus DNA,termina[repeats, J. Virol., 44, 330, 1982. 410. Modak, M. ft. and Marcus, S. L., Specific inhibition of DNA polymerase-associated RNase H by t DNA, d. Virol.,22, 243, 1977. 411. Modak, M. J. and Marcus, S. L., Purification and properties of Rauschet leukemia virus DNA polymerase and selective inhibitiort of mammalian viral reverse transeriptase by inorganic phosphate, J, Biol. Chein.,252, fl, 1977. 412. Moelljng, K., Characterization of reverse transcriptase and RNase H from Friend-marine leukemia virus, Virology, 62, 46, 1974. 413. Moelling, K., Further characterization of the Friend murine leukemia virus reverse transcriptaseRNase H complex, J. Virol., 18, 418,1976. 414. Moll, B., Hartley, J. W., and Rowe, W. P., Induction of B-tropic and N-tropic murine leukemia virus frotn BI0.BR/SgLi mouse embryo cell lines by 5-iodo-2'-deoxyuridine, L Natl. Cancer Inst., 63,213,1979. 415. MiSlling, K., Bolognesi, D. P., Bauer, H., Bustn, W., Plassmann, H. W., and Hausen, P., Association of viral reverse transeriptase with an enzyme desrading the RNA moiety of RNA-DNA hybrids, Nat. (London)N_ Biol., 234, 240, 1971. 416. Moloney, J. B., Biological studies on a lymphoid-leukemia virus extracted from Sarcoma 37. I. Origin and introductory investigations, J. Natl. Cancer Inst., 24, 933, 1960. 417. Moloney, J. B., Properties of a leukemic virus, Natl. Cancer Inst. Monogr., 4, 7~ 1960. 418. Moloney, J. B,, The murine leukemias, Fed. Pror 21, 19, 1962, 419. Monroy, G., Jacquet, J., Groner, Y., and Hurwitz, J., AMV RNA transcription in cell.free systems and properties of in vitro chromatin-direeted RNA synthesis, Cold Spring Harbor Syrup. Quant. BioL, 39,1033,1974. 420. Montagnier, L., Gold/r, A., and Vigier, P,, A possible sabuait structure of Rous sarcoma virus RNA, Z Gun. Virol., 4, 449, 1969, 421. Montelaro, R. C., Sullivan, S. J., and Bolognesi, D. P., An analysis of type-C retrovirus pob'peptides and their association in the virion, Virology, 84,19, 1978. 422. More~tu-Oachelin, F., Robert-Lezenes, J., Wendling, F., Tavitian, A., and Tambourin, P., Integration of spleen focus-forming virus proviruses in Friend tumor cells, J. ViroI., 53,292, 1985. 423. Mueller-Lantzsch, N. and Fan, H,, Monospecifir immunoprecipitation of routine leukemia virus polyribosomes: identification of p30 protein-specific messenger RNA, Ceil, 9,579, 1976. 424. Murphy, E. C., Jr. and Arlinghaus, R. B., Cell-free synthesis of Rauscher marine leukemia virus "gag" and "gag-pol" precursor polyproteins from virion 35 S RNA in a mRNA-dependent translation system derived from mouse tissue culture cells, Virology, 86, 329, 1978. 425. Murphy, E. C., Jr., Carnpos, I11, D., and Adinghaus,' g. B., Cell.free synthesis of Rauscher marine leukemia virus "gag"and "env"gene products from separate cellular mRNA species, Virology, 93, 293,1979. 426. Murphy, E. C., Jr., Kopchick, J. J., Watson, K. F., and Arlinghaus, R. B., Cell-free synthesis of a precursor polyprotein containing both gag and pol gone products by Rauscher routine leukemia virus 35S RNA, Cell, 13,359, 1978. 427. Murphy, E. C., Jr., Wills, N., apd Arlinghaus, R. B., Suppression of routine retrovirus polypeptide termination: eifect of amber suppressor tRNA on the cell-free translation of Rauscher murine leukemia virus, Moloney marine leukemia virus, and Motoney murine sarcoma virus 124 RNA, J. ViroL, 34, 464, 1980. 428. Murphy, J. B., The effect of.castration, theclin, and testosterone on the incidence of leukemia in a Rockefeller Institute strain of mice, Cancer Res., 4,622,1944. 429. Murray, M. J., Cunningham, J. M., Parada, L. F., Damry, F., Lebowitz, P., and Weinberg, R. A., The HL.60 transforming sequet~ee: a rasoneogene coexisting with altered mycgenes in hematopoietic tumors, Cell, ~3,749, 1983.

310

C R C Critical Reviews in O n c o l o g y / H c m a t o l o g y

430. Murti, K, G., Bondurant, M,, and Tcreba, A,, Secondary structural features in the 70S RNAs of Moloney murine leukemia and Rous sarcoma viruses as observed by electron microscopy, J. Vffol., 37, 411, 1981. 431. Naso, R. B,, Areement, L. 3,, and Arlinghaus, R. B., Biosynthesis of Rauscher leukemia viral proteins, Cell, 4, 31, 1975. 432. Naso, R. B., Arcement, L. J,, Karshin, W, L., ffamjoom, G. A., and Arlinghaus, R. B., A fucosedeficient glycoprotein precursor to Rauscher leukemia virus gp69/71, Proc. Natl. Acad. ScL U.S.A., 73, 2326, 1976. 433. Naso, R. B., Arcement, L. J., Wood, T. G., Suunders, T, E., and Arlinghaus, R. B., The cell-free translation of Rauscher leukemia virus RNA into higl~ molecular weight polypeptides, Biochim. Biophys. Acta, 383,195, 1975. 434. Naso, R. B., Karshin, W. L., Wfi, Y. H., and Arlinghaus, R. B., Characterization of 40,000- and 25,000.dalton intermediate precursors to Rauscher murine leukemia virus gaggene products, J. Vi. rol., 32, 187, 1979. 435. Naso, R. B., Wang, C. S., Tsai, S., and Aflinghaus, R. B., Ribosomes from Raascher leukemia virus-infected cells and their response to Rauscher 'dral RNA and potyuridyllc acid, Biochim. Bio. phys. Acta, 324, 346, 1973., 436. Neel, B, G., Hayward, W. S., Kobinson, H. L., Fang, J., and Astrin, S. M., Avian leukosis virusinduced tumors have common proviral integration sites and synthesize discrete new RNAs: oncogenesis by promoter insertion, Cell, 23.323, 1981. 437. Niman, H. L. and Elder, J. H,, Molecular dissection of Rauseher virus gp70 by using monoclonal antibodies: localization of acquired sequences of related envelope gene recombinants, Proc. Natl. Acad. Scl. U.S.A., 77, 4524, 19g0. 438. Nissen-Meyer, 3. and Nes, 1, F,, Characterization of an endonuelease activity associated with Friendmurine leukemia virus, Bioehim. Biophys. Acta, 609, 148, 1980. 439. Nissen-Me~er, J. and Nes, I. F., Purification and properties of DNA endonuclease associated with Friend leukemia virus, Nucleic Acids Res., 8, 5043, 1980. 440. Nooter, K~ and Bentvelzen, P., In vitrogrowth characteristics of viraIIy transformed routine myelold ceils, Cancer Res., 36, 1246, 1976, 441. Nowinskl, R. C. and Hays, E. F., Oncogenieity of AKR endogenous leukemia viruses, J. Virol., 27, 13, 1978. 442. Nusse, R., van Ooyen, A., Cox, D., Fung, Y. K. T., and Va~'mus, H., Mode of provlral activation of aputativemammary oncogene(int, l)onmouseehromosom~.15 Nature(London) 307,131, 1984. 443. Nusse, R. and Varmus, H. E., Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome, Cell, 3 I, 99, 1982. 444, Odaka, T., lkeda, H., and Akatsuka, T., Restricted expression of endogenous N-tropic XC-positive leukemia virus in hybrids between G and AKR mice: an effect of the Fv-a gene, Int. J, Cancer, 25, 757, 1980. 445. Odaka, T,,/keda, H., Moriwaki, K., Matsuzawa, A., Mizuno, M., and Konda, K., Genetic resistance in Japanese wild mice (Mus musculus molossinus) to an NB-tropic Friend marine !eukemia virus, J. Natl. Cancer lust., 61, 1301, 1978. 446. Odaka, T., lkeda, H., Yoshikura, H,, Morikawi, K., and Suzuki, S., Fv-4:gene controlling resistance to NB-tropic Friend murine leukemia virhs. Distribution in wild mice, introduction into genetic background of BALB/c mice, and mapping of chromosomes, J. Natl. Cancer Inst., 67.1123, 1981. 447. Odaka, T. and Yamamoto, T., Inheritance of susceptibility to Friend mouse leukemia virus, Jpn. J. Exp, Med., 32, 405, 1962. 448. O'Donnell, P. V., Deitch, C, J., and Pincus. T., Multiplicity-dependent kinetics of murlne leukemia virus infection in Fv.l-sensitivr and Fv-l-resistant ceils, Virology, 73, 23, 1976. 449. O'Donnell, P. V, and Nowinski, R. C., Serological analysis of antigenic determinants on the envgene products of AKR dualtropic (MCF) murine leukemia viruses, Virology, 107, gl, 1980, 450. O'Donnell, P. V., Stockert, E., Obata, Y., and Old, L, J.. Leukemogenic properties of AKR dualtropic (MCF) viruses: amplification of morine leukemia virus-related antigens on thymocytes and acceleration of leukemia development in A K R mice, Virology, 112, 548, 1981. 451. Oie, H. K,, Gazdar, A. F., Lalley, P. A., Russell, E. K., Minna, J. D., DeLarco, J., Todaro, G. J., and Francke, U., Mouse chromosome 5 codes for ecotropic murine leukaemia virus cell4urface receptor, Nature (London), 274, 60, 1978. 452. Old, L. 3, and Stockert, E., Immanogenetics of cell surface antigens of mouse leukemia, Annu. Rev, Genet., 17, 127, 1977. 453. Oldstone, M. B. A., Jensen, F., Dixon, F. J., and Lampert, P. W., Pathogenesis of the slow disease of the central nervous system associated with wild mouse virus. II. Role of virus and host gene products, Virology, 107. 180, 1980.

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454. O)dstone, M. B. A., Jensen, F., Eider, J,, Dixon, F. J., and Lampert, P. W., Pathogenesis of the slow disease of the central nervous system associated with wild mouse virus. Ill. Role of input virus and MCF recombinants in disease, Virology, 128, 154, 1983. 455. Oldstone, M. B. A,, Lampert, P. W,, Lee, S., a~d Dixon, F. J., Pathogenesis of the slow disease of zhe central nervous system associa(ed with WM 1504 E virus. I. Relationship of strain susceptibility and replication to disease, Am. J. PathoL, 88,193,1977. 456. O|iff, A., Co)lins, L., and Mirenda, C,, Molecular cloning of Friend mink cell focus-inducing virus: identification of mink cell focus-inducing virus-like messages in norma~ and transformed calls, J, ViroL, 48, 542, 1983. 457. Otiff, A. l., Hager, G.'L., Chattg, E, H., Scolnick, E. M., Chart, H, W., and Lowy, D. R., Transruction of molecularly cloned Friend murine leukemia virus DNA yields a highly leukemogenic helperindependent type C virus, J. Virol,, 33,475, 1980. 458. Oliff, A., Linemeyer, D,, Ruscetti, S., Lowr R., Lowy, D. R., and Scolnick, E., Subgenomjc fragment of molecularly cloned Friend muri~te leukemia virus DN'A contains the gene(s) responsible for Friend murine leukemia virus.induced disease, J. Vi[oI,, 35, 924, 1980. 459. Oliff, A., McKinney, M. D., and Agranovsky, O., Contribution of the gagand polsequences to the leukemogenicity of Friend routine leukerttia virus, J. VlroL, 54, 864, 1985. 460. Oliff, A., Oliff, I,, $chmidt, B,, and Famulari, N., lsolation~of immortal cell lines from the fits! stage of murine leukemia vir~s.induced leukemia, Prec. Null. Acad. Sci. U.S.A., 81, 5464, 1984. 461. Oliff, A. and Ruscetti, S., A 2A.kilobase-pair fragmen~ of the Friend marine le~Aemia virus genome contains the sequences responsible for Friend marine leukemia virus-induced erythroleukemia, J. ViroL, 46, 718, [983. 462, Oliff, A., R'ascetti, S., Douglass, E. C,, andSco]nick, E., Isolation of transplantable erythroleukemia cells from mice infecled with helper.independent Friend murine ]eukemia virus, Blood, 58, 244,1981. 463, Oliff, A., Signorr K., and Collins, L., The envelope gene and long Tterminal repeat sequences contribute to the ~athogenic phenotype of helpr Friend viruses, .L Virol., 51,788,1984. 464. O'Neill, R. g., Buckler, C. E., Theodore, T. S.. Martin, M. A., and gepaskr R., Envelope and long terminal repeat sequeoces of a .cloned infectious NZB xenotropic routine leukemia virus, J. Virol., 53,100,1985. 465, Oroszlan, S,, Henderson, L. E., Stephenson, J, R., Copeland, T, O,, Long, C. W., lhle, J. N., and Gilden, R. V., Amino- and carboxyl.terminai amino acid sequences of proteins coded by gaggene of mur/ne leukemia virus, Proc. Natl. Acid. ScL U.S.A,, 75, 1404, I978. 466. Oroszlan, S., Long, C, W., and Gilden, R. V., Isolation of a marine type-C virus p30 precursor protein by DNA-celtulose chromatography, Virology, 72, 523, 1976. 467. Oskarsson, M,, McClements, W. L., Blair, D, G., Matzel, J, V,, and Vande Woude, G. F.., Properties of a normal mouse cell DNA sequence (sure) homologous to the src sequence of Moloney sarcoma virus, Science, 207, 1222, 1980. 468. Ostertag, W., Vehmeyer, K,, Fagg, B,, Pragnell, I. B., Paetz, W., Le Bousse, M. C., Smad~a.Joffe, F., Klein, B., arasmin, C., aM Eiscn, H., Myeloproliferative virus, a cloned routine sarcoma virus with spleen focus-forming properties in adult mice, J. Virol., 33,573, 1980. 469. Padgett, T. G., Stubblefield, E., and Varmus, H. E., Chicken macrochromosomes contain an endogenous provirus and microchromosomes contain sequences related to the transforming gene of ASV, Cr 649, 1977. 470. Pal, B. K., MeAliister, g. M., Gardner, M. B., and Roy-Burman, P., Comparative studies on the structural phosphoproteins of mammalian type C viruses, J. Virol., 16, 123, 1975. 471. Pal, B. K. and Roy-Burman, P., Phosphoproteins: structural components of oncornaviruses, J. Vi. tel., 15,540, 1975. 472. Palmiter, R. D., Gagnoa, J,, Vogt, V. M., Ripley, S., and Eisenman, R. N., The NHrterminal sequence of the avian oncov[rus gag precursor potyproteirt (Pr?6,',), Virology, 91,423, 1978. 493. Panem, S. nnd Kirsten, W. H., Rdease of mouse leukemia-sarcoma virus from synchronized ceils, Z Natl. Cancer Insl., 50, 563~ 1973. 474. Panet, A., Gorecki, M., Bratosin, S., and Aloni, Y., Electron microcopic evidence for splicing of Moloney murine leukemia virus RNAs, Nucleic Acids Res., 5, 3219, 1978. 475. Panganiban, A. T. and Temin, H. M., The retrovirus l~olgene encodes a product required for DNA integration: identification e r a retrovirus intlocus, Proc. Null. Acad. Sci. U.S.A., 81, 7885, 1984. 476, Parsons, J, T., Coffin, J. M., Haroz, R. K., [Iromley, P. A., and Weissmann, C., Quantitative determination and location of newly synthesized virus-specific ribonucleic acid in chicken cells infected with Rous sarcoma virus, J. ViroL, I1,761,197], 477. Paskind, M. P., Weinbcrg, R. A., and Baltimore, D,, Dependence of Moloney marine leukemia virus on cell grewth, Virology, 67,242, 1975, 478. Paterson, B, M., Mareiani, D. J., and Papas, T. S., Cell-free synthesis of the precursor 1~olypeptide for avian myeloblastosis virus DNA polymerase, Prec. NarL Acad. Sci, U.S,A., "/4, 4951, 1977.

312

C R C Critical R e v i e w s in O n c o l o g y / H e m a t o I o g y

479. Pawson, T., Harvey. R., and Smith, A. E,, The size of Runs sarcoma virus mRNAs active in cellfree translation, Nature (London), 268,416, 1977, 480. Pawson, T., Martin, G. S., and Smith, A. E., Cell-free translation of virion RNA from nondefective and transformation-defective Rous sarcoma viruses, 3". ViroL, 19,950, 1976. 481. Pawson, T., Mellon, P., Duesberg, P. !--I., and Martin, G. S., ear gone of Rous sarcoma virus: identification of the gone product by cetl-free trans]ation, J. ViroL, 33,993, 1980. 482. Payne, G. S., Bishop, J. M., and Varmus, !-I. E., MultipIe arrangements of viral DNA and an activated host oncogene in bursal Iymphomas, Nature (London), 295, 209, 1982. 483. Pedersen, V. S., Crowther, R. L., Tenney, D. u Reimold, A. M., arid Haseltine~ W. A., Novet leukaemogenic retroviruses isolated from cell line derived from spontaneous AKR tumour, Nature (London), 292, 167,1981. 484. Perez-.Bercoff, R. and Billeter, M. A., Characterization of the 3'-terminal region of the large molecular weight RNA .subunits from normal and transformation-defective Rous sarcoma virus, Biochim. Biophys. Acta, 454,383, I976. 485. Peters, G., Brookes, S., Smith, R,, aI~d Dickson, C,, Tumorigenesis by mouse mammary tumor virus: evidence for a common region for pruritus integration in mammary tumors, Cefl, 33,369, 1983. 486. Peters, G. and Dahlberg, J. E., RNA-directed DNA synthesis in Moloney murine teukemia virus: interaction between the primer tRNA and the genuine, RNA, J. Virol., 31,398, I979. 487. Peters, G., Harada, F., Dah[berg, J. E., Panet, A., Haseltine, W. A., and Baltimore, D., Lowmolecular-weight RNAs of Moloney routine leukemia virus: identification of the primer for RNA. directed DNA synthesis, J. ViroL, 21, 1031, 1977. 488. Peters, R. L., Hartley, J, W., Spahn, G. J., Rabstein, L. S,, Whitmire, C. 13., Turner, H. C., and Huebner, R. J., Prevatence of the group-specific (gs) antigen and infectibus virus expressions o• the routine C-type RNA viruses during the life span of BALB/cCr mice, Int. J. Cancer, 10, 283, 1972. 489. Peters, R. L., Spahn, G. J., Rabstein, L. S., Kr G. J., and Huebner, R. J., Murine C-type RNA virus from spontaneous neoplasms: in vitro host range and oncogenic potential, Science, 18I, 665, 1973. 490. PhiIipson, L., Andersson, P,, Olshevsky, U., Weinberg, R., Baltimore, D., and Gesteland, R., Tt'anslatiort of MuLV and MSV RNA's [r~ rtucIease-treated re~iculoeyte extracts: enhancement of the gag-polpolypeptide with yeast suppressor tRNA, Co11,13, 189, 1978. 491. Pincus, T., Hartley, J. W., and Rowe, W. P., A major genetic locus affecting resistance to infection with routine [eukemia viruses. 1. Tissue culture studies of naturally occurring viruses, J. ~.xp. Meal., 133, I219, 1971. 492. Pincus, T., Hartley, J. W., and Rowe, W. P., A major genetic locus affecting resistance to infection with murine leukemia viruses. IV. Dose-response relationships in Fv-i sensitive and resistant cell cultures, Virology, 65,333,1975. 493. Pincus, T., Rowe, W. P., and Lilly, F., A major genetic Incus affecting resistance to infection with murine leukemia viruses. !I.. Apparent identity to a major locus described for resistance to Friend ~irus, J. Exp. MecL, 133,1234, t971. 494. Pinter, A. and Fleissner, E., The presence of disulfide-linked gpT0-plS(E) complexes in AKR routine leukemia virus, Virology, 83,417, 1977. 495. Pinter, A., Lieman-Hurwitz,'J., and Fleissner, E., The nature of the association between the routine leukemia virus envelope proteins, Virology, 91, "345,1978. 496. Pluznik, D. H. and Sachs, h., Quantitation of a routine leukemia virus with a spleen colony assay, J. Natl. Cancer Inst., 33,535, 1964. 497. Potter, M., Sklar, M. D., ~tnd Rowe, W. P., Rapid viral induction of pl~snaacytomas in pristaneprimed BALB/c mice, Science, 182, 592, 1973. 498. Pratt, D. M., Strominger, J., Parkman, g., Kaplan, D., Schwaber, J., Rosenb9 N., and Scher, C. D., Aheison virus-transformed tymphocytes: null ceils that modulate H-2, Cell, 12, 683,1977. 499. Pr,:mkumar, E., Potter, M,, Singer, P. A., and Sklar, M. D., Synthesis, surface deposition, and secretion of Jmmnnoglobulins by Abelson virus-~ransformed lymphosarcoma cell lines, CeII, 6, I49, 1975. 500. Purchio, A. F., Erikson, E., Brugge, J. S., and Erikson, R. L., Identification of a polypeptide encoded by the avian sarcoma virus srcgene, Proc. Natl. Acad. Sci. U.S.A., 75,1567, 1978. 501. Purchio, A. F., Erikson, E., and Erikson, R. L., Translation of 35S and of subgenomic regions of avian sarcoma virus RNA,,Proc. Natl. Acad, Sci. U.S.A., 74, 4661,1977. 502. Purchio, A. F,, jovanovich, S., and Erikson, R.: L,, Sites of synthesis of viral proteins in avian sarcoma virus-infected chicken ceils, ,f. Viral., 35, 629, I980. 593. gabstein, L. S., Gazdar, A. F., Chopra, H. C., and Abelson, H. T., Early morp~oto&ica! changes associated with infection by a murine nonthymic lymphatic tumor virus, .I. Natl. Cancer Inst., 46,

481, 1971. 504. Racevskis, J. and Koch, G.~ Viral protein synthesis in Friend erythroleukemia cell lines, J. ViroL, 21, 328,1977.

V o l u m e 5, Issue 3

313

505. Rands, E.,.Lowy, D. R., Lander, M. R., and Chattopadhyay, S. K., Restriction endonuclease mapping of ecotropic touring leukemia viral DNAs: size and sequence heterogeneity of the long terminal repeat, Virology, 108,445, 1981. 506. Raschke, W. C., Ralph, P., Watson, J'., SkIar, M., and C~on, H,, Oncoge~ic transformation of murine lymphoid cells by in vitro infection with Abeison leukemia vials, 1. Natl. Cancer Inst., 54, 1249, 1975. 507. Rasheed, So, Gardner, M. B., and Chart, E., Amphotropic host range of naturally occurring wild mouse leukemia virus, J. V/rol., I9, 13,1976. 508. Rasheed, S., Toth, E., and Gardner, M. B., Characterization of purely ecotropic and amphotropic naturally occurring wild mouse leukemia viruses, Intervitology, 8,323, 1977. 509. Rassart, E., Sankar-Mistry, P., Lemay, G,, DesGroseiilers, L., and Jolicoeur, P., New class of leu. kemogenic ecotropic recombinant muting leukemia virt~s isolated from radiation-induced thymomas of C57BL/6 mice, J. ViroL, 45, 565, 1983. 510. Rauseher, F. J., A virus-induced disease of mice characterized by erythrocytopoiesis and lymphoid leukemia, J. Natl. Cancer lust., 29, 515,1962. 511. Ruddy, E. P., Dunn, C. Y., and Aaronson, S. A., Different lymphoid cell targets for transformation hy replication-competent Mol~ney and Rauseher mouse leukemia viruses, Ceil, 19, 663, 1980. 512, Reddy, E. P., Smith, M. J., and Srinivasan, A., Nucleotide sequence of Abelson touring leukemia virus genome: structural similarity of its transforming gene product to other oncgene products with tyrosine-specific kinase activity, Proc. Natl. Acad. Sci. U.S.A., 80, 3623, I983. 513. Rein, A., interference grouping of muting leukemia viruses: a distinct receptor for the MCF-reeombinant viruses in mouse ceils, Virology, I20,251, 1982. 514. Rein, A., Schultz, A. M., Bader, J. P., and Bassin, R. H., lnhibitors of glycosylation reverse retroviral imerference, Virology, I 19, 185, 1982, 515. Repaske, R., O'Neill, R, R., Kahn, A. S., and Martin, M. A., Nucleofide sequence Of the ear-specific segment of NFS-Th-1 xenotropic muting leukemia virus, J. Virol., 46, 204, i983. 516. Reuben, R. C., Rilkind, R. A., and Marks, P. A., Chemically induced routine erythroleukemic differentiation, Biochim. Biophys. Acid, 605,325, 1980. 517. Reynolds, F. H., Jr., Sacks, T. L~, Deobagkar, D. N., and Stephenson, J. R., Cells non-productively transformed by Abelson touring leukemia virus express a high molecular weight po[yproteir~ containing structural and nonstructural components, Proc. NatL Acad. ScL U.S.A., 75, 3974, 1978. 518, Reynolds, R. K. and Stephenson, J. R., lntracistronic mapping of the muting type C viral gaggene by use of conditiona] lethal replication mutants, Virology, 81,328, I977. 519. Rho, H, M. and Green, M., The homopolyadenylate and adjacent nucleotJdes at the 3'.terminus of 30-40S RNA subunits in the genome of murine sarcoma-leukemia virus, Proc. Nail. Acad. Sci. U.S.A., 71, 2386, 1974. 520. Rich, M. A., Siegler, R., Karl, S., and Ctymer, it., Spontaneous regression of virus induced muting leukemia. I. Host-virus system, J. Natl. Cancer Inst., 43, 559, 1969. 521. Riflfn, D. B. and Quigley, J. P., Virus-induced modification of cellular membranes related to viral structure, Anna. Rev. Microbiol., 28,325, 1974. 522. Riggin, C. H., Bondurant, M., and Mitchell, W. M., Physical properties of Moloney touring leukemia virus high-molecular-weight RNA: a two subunit structure, 3. Virol., 16, 1528, I975. 523. ~dman, J. and Beaudreau, G. S., Viral DNA-dependertt DNA polymerase and the properties of thymidine labelled material in virions of an oncogenic RNA virus, Nature fLondon), 228,427,1970. 524. Ringold, G. M., Shank, P. R., Varmus, H. E,, Ring, J., and Yamamoto, K. R., Integration and transcription of mouse mammary virus DNA in rat hepatoma cells, Proc. Natl. Acad. $ci. U.S.A., 76,665, 1979. 525. Risser, R., Friend erythroleukemia antigen. A viraI antigen specified by spleen focus-forming virus and differentiation antigen controlled by the Fv.21ocus, 1. Exp. Mud., 1,19, 1152, 1979. 526. Risser, R., Potter, M., and Rowe, W. P., Abelson virus-induced lymphomagenesis in mice, J. Exp. Mud., 148, 7]4, 1978. 527. Risser, R., Stockert, E., and Old, L. J., Abelson antigen: a viral antigen that is also a differentiation antigen of BALB/c mice, Proc. Natl. Acad. Sci. U.SIA., 75, 3918, 1978, 528. Robbins, K. C.. Cabradilla, C. D., Stephenson, J. R,, and Aaronson, S. A., Segregation of genetic information for a B-tropic leukemia virus with the structural locus for BALB: virus-l, Proc. Natl. Acad. Sci. U.S.A.,74t 2953,1977. 529. Robey, W. G., Oskar~son, M. K., Vande Woude, G. F., Naso, R. B., Arlinghaus, R. B., Haapala, D. K., and Fischinger, P. J., Ceils transformed by certain strains of Moloney sarcoma virus contain touring p60, Cell, 10, 79, 1977. 530. Robin, M. S,, Saizberll, S,, and Green, M., Cytoplasmic synthesis of viral DNA r during infection and cell transformation by ihe touring sarcoma leukemia virus, Intervirology, 4,268, 1974.

314

C R C Critical Reviews in O n e o l o g y / H c m a t o t o g y

531. Robinson, H. L., Blais, B. M,, Tsichlis,P. N., and Coffin, J. M., At tease two regions of the vira] genuine determine the oncogenic potential of avian leukosis viruses, Proc. Natl. Acad. Sci. U.S.A., 79, 1225, 1982. 532, Robinson, H, L,, Pearson, M. N., DeSimone, D. W., Tsichiis, P. N., and Coffin, J. M., SubgroupE avian-ieukosis-virus..associated diseases in chickens, Cold Spring Harbor Syrup. Quint. Biol., 44, 1133, 1979. 533. Robinson, W. S., Pitkanen, A., and Rubin, H., The nucleic acid of the Bryan strain of Rous sarcoma virus: purification of the virus and isolation of the nuc1r acid, ProF. Natl. Acad, Sci. U.S.A., 54, 137, 1965, 534. Robinson, W. S., Robinson, H. L,, and Duesberg, P. H,, Tumor virus RNA's, Proc. Nod. Acad. Sci. U.S.A., 58,825, 1967. 535. Rommetaere, J., Duals-Keller, H., anti Hopkins, N., RNA sequencing provides evidence for aIielism of determinants of the N-, B- or NB-tropism of routine leukemia viruses, Ceil, 16, 43,1979, 536, Rommelaere, J., Failer, D. V., and Hopkins, N., Characterization and mapping of RNase Tl-resistant otigonucteotides derived from the genomes of AKV and MCF murine leukemia viruses, Proc. Natl. Acad, Sci. U.S.A,, 75,495, 1978. 537. Rose, J. K., Haseltine, W. A,, and Baltimore, D., 5'-terminus of Moloney marine leukemia virus 35S RNA is m'G"pp#'GmpCp, l. Virol., 20, 324, 1976. ~38. gosenberg, N. a~d Baltimore, D., A quantitative assay for transformation of bone marr~3w ceils by Abelson murine leukemia virus, Y. Exp. Mad., 143, 1453, 1976. 539. Rosenberg, N., Baltimore, D., and Scher, C. D., In vitro transformation of lymphoid cells by Abelson murine leukemia virus, Proc. Natl. Acad, Sd. U.S.A., 72, 1932, 1975. 540. Rosenberg, N. E., Clark, D. R., and Witte, O. N,, Abelson marine leukemia virus mutants deficient in kinase activity and lymphoid cell transformation, J. V#ol., 36, 766,1980. 541. Rosenberg, N., Siden. E., and Baltimore, D., Synthesis of mu chains by Abelson virus-transformed ceils and imtuction of light chain synthesis with lipopotysacchari~e, ia B Lymphocytes in the Immune Response, Cooper, M., et al., Eds., Elsevier, New York, 1979, 379. 542. Rosenberg, N. and Witte, O. N., Abelson marine leukemia virus mutants with alterations in the virusspecific PI20 molecule, J. Virol., 33,340, 1980. 543, Rusher, M. R., Grinna, L. S., and Robbins, P. W., Difference in glycosylation patterns of closely related marine leukemia viruses, Proc. Nat/. Acad. gel. U.S.A., 77, 67, 1980. 544. Rusher, M, R., Tung, J.-S., Hopkins, N., and Robbins, P, W., Relationship of G,x antigen expression ~o the glycosyltition of marine leukemia virus glycoprotein, Proc. Nod. Acad, Sci. U.S.A., 77, 6420, 1980, 545. Ross, J., Scoinick, E. M,, Todaro, G. J., and Aaronson, S. A., Separation of murine cellular and routine leukaemia virus DNA polymerases, Nat. (London) N. Biol., 231,163,1971. 546. Rossi, G. B. and Peschle, C., Enhanced proIifetation and migration of BFU.E, and erythropoietinindependence of CFU-E expression in FLY-infected mice: comparative studies on anemic and polycythemic strains, in In Viro and In Vitro Erythropoiesis: The Friend System, Rossi, G. B,, Ed., ElsevieL New York, 1980,139. 547. Rothenberg, E., Donoghue, D. J'., and Baltimore, D., Analysis of a 5" leader sequence on marine leukemia virus 2IS RNA; heteroduplex mapping with long reverse transcriptase products, Cell, 13, 435, 1978. 548. Rousse], M., Saule, S., Lagrou, C., Rommens, C,, Beug, H., Graf, T., and Stehelin, D., Three new types of viral oncogene of cellular origin specific for heamatopoietic cell transformation, Nature (London), 281,, 452, 1970. 549. Rowe, W. P., Studies of genetic transmission of marine leukemia virus by AKR mice. I. Crosses with FV.I" strains of mice, J. Exp. Mad., 136,1272,1972, 550. Rowe, W. P., Genetic factors in the natural history of marine leukemia virus infection: G. H. A. Clowes Memorial Lecture, Cancer Rest., 33, 3061,1973. 551. Rowe, W. P. and Pincus, T., Quantitative studies of naturally occurring marine leukemia virus infection of AKR mice, Z Exp. Me(/., 135,429,1972. 552. gud
V o l u m e 5, E s u e 3

315

556. Ruta, M, and Kabat, D., Plasma membrane glycoproteins encoded by cloned Rausher and Friend spleen focus-forming viruses, J. Virol., 35, 8,14, 1980. 557. Rymo, L., Parsons, I. T., Coffin, J. M., and Weissmann, C,, In vitro synthesis of Rous sarcoma virus.specific RNA is catalyzed by a DNA-depcndent RNA polymesase, Proc. Natl. Aead. SeL U,S,A., 71, 2782, 1974. 558. Snbran, J. L., Hsu, T. W., Ycnter, C., Knit, A., Mason, W, S., and Taylor, J. M., Analysis 01 integrated avian RNA tumor virus DNA in transformed chicken, duck, and quail fibroblnsts, J. ViroL, 29, 170, 1979, 559. Sakaguchi, A. Y., Lalley, P. A., and Naylnr, 6, L., Human and mouse cellular myc protooncogencs reside on chromosomes involved in numerical and structural aberrations in cancer, somat. Cell Ge. net.,9, 391, 1983, 560. Salden, M., Asselbergs, F., and Bloemendal, H., Translation of oneogenic virus RNA in Xenopus laevisoocytes, Nature (London), 259, 696, 1976. 56I. Sa[zberg, S., Robin, M. S,, and Green, M., Appearance of virus-specific RNA. virus particles, and cell surface changes in cells rapidly transformed by the mnrlne sarcoma virus, Virology, 53) 186, 1973. 562. Samuel, K. P., Papas, T. S.) and Chirikj!an, J. G,, DNA endonucieases associated with the avian myeloblastosis virus DNA polymerase) Proc. Natl. Acad, SoL U.S,A., 76, 2659, 1979. 563. Sarma, P. S., Cheong, M. P., Hartley, J. W., and Huebner, R. J., A viral interference test for mouse leukemia viruses, Virology, 33,180, 1967. 564. Sassa, S., Takaku, F., and Nakao, K., Regulation of erythropoiesis in the Friend leukemia mouse, Blood, 31,758, 1968. 565. Sato, H. and Boyse, E, A., A new alloantigen expressed selectively on B cells: the Lyb-2 system, Immunogenetics, 3,565, 1976. 566. Sawyer, R. C. and Dahlberg, J. E,, Small RNAs of Runs sarcoma virus: characterization by twodlmensJona] polyaerylamide gel electrophoresis and fingerprint analysis, J. ViroL, 12, 1226, 1973. 567. Sawyer, R. C,) Harada, F., and.Dahlberg, J. E,, Virlon-associated RNA primer for Rous sarcoma virus DNA synthesis: isolation from uninfected cells, J, ViroL, 13, 1302, 1974. 568. Sober, C. D. and Sieglec, g., Direct transformation of 3T3 cells by Abelson murine leukaemia virus, Nature (London), 253,729, 1975. 569. Schiff, R. D. and Grandgenett, D. P., Virus-coded origin of a 32,000-dalton protein from avian rctrovirus cores: structural relatedness of p32 and the/J polypeptide of the avian retrovirus DNA polymeruse, J. ViroL, 28,279, 1978. 570. Schincariol, A. L. and Joklik, W. K., Early synthesis of virus-specific RNA and DNA in cells rapidly transformed with Runs sarcoma virus, Virology, 56, 532, 1973, 571. Sehiodler, J., Hynes, R., and Hopkins, N., Evidence for recombination between N- and B-troplc murine leukemia viruses: analysis of three virion proteins by sodium dodecyl sulfate.polyaerylamide gel electrophoresis, J. ViroL, 23, 700, 1977. 572. Schoolman, H. M., Spurrier, W., Schwartz, S. O., and Szanto, P. B., Studies in leukemia. V[. The induction of leukemia virus in Swiss mice by means of cell-free filtrates of leukemic mouse brain, Blood, 12, 694, 1957. 573. Schulein, M., Burnette, W. N., and August, J. T., Stoichiometry and specificity of binding of Rauscher oncovirus 10,000.da[ton (pl0) structural protein to nucleic acids, J. ViroL, 26, 54, 1978. 574. Schultz, A. M., Lockhart, S. M.) Rabin, E. M., and Oroszlan, S., Structure of glycosylated and unglyeosylated gagpolyproteins of Rauscher murine leukemia virus: carbohydrate attachment sites, J. ViroL, 38, 581, 1981. 575. Schultz, A. M. and Oroszlan, S., Murine leukemia virus gagpolyproteins: the pnptide chain unique to Pr80 is located at the amino terminus, Virology, 91,481, 1978. 576. Schultz, A, M., Rabin, E. H., and Oroszlan, S., Post-translation modification of Rauschec leukemia virus precursor polyproteins encoded by the &~'gene, .L Virol., 30) 255, 1979, 577. Schwartz, D. E., Tizard, R., and Gilbert, W., Nucleotide sequence of Rous sarcoma ~irus, Cell, 32, 853, 1983. 578. Schwartz, D. E., Znmecuik, P. C., and Weith, H. L., Rous sarcoma virus genome is terminally redundant: the 3' sequence, Pro(:. Natl. Acad. Sei. U,S.A., 74, 994, 1977. 579. Schwartzberg, P., Collcelll, J., and Golf, S. P., Construction and analysis of deletion mutations in the polgene of Moloney murine leukemia virus: a new viral function required for productive infection, Cell, 37,1043, 19114. 580. Scolniuk, E. M. and Parks, W.'P., Harvey sarcoma virus: a second murine type C sarcoma virus with rat genetic information, J. Virof., 13, 1211, 1974. 581. Scolnick, E, M., Rands, E. Williams, D., and Parks, W. P., Studies on the nucleic acid sequences of Kirsten sarcoma virus: a model for formation of a mammalian RNA-contuining sarcoma virus, J, Virol., 12, 458, 1973.

3 16

C R C Critical R e v i e w s in O n c o l o g y / H e m a t o l o g y

582. Scolnick, E. M., Weeks, M. O., Shib, T. Y., Ruscettl, S. K., and Dexter, T. M., Markedly elevated levels of an endogenous sara protein in a hematopoietic precursor cell line, Mol. Cell. Biol., I, 66, 1981. 583. Scott, M. L., McKereghan, K., Kaplan, H. S., and Fry, K. E., Molecular cloning and partial characterlzatlon of unintegrated linear DNA frmn gibbon ape leukemia virus, Proc. N&.'I. Acad. ScL U.S,A., 78, 4213, 1981. 584. Sefton, B. M., Hunter, T., and Raschke, W. C., Evidence that the Abelson virus protein functions in viva as a protein kinase that phosphorylates tyrosine, Proc. Natl. Acad. Sr U.S.A., 78, 1552, 1981. 585. Sen, A., Sherr, C. J., and Todmo, G. J., Specific binding of the type C viral core protein p12 with purified viral RNA, Cell, 7, 21, 1976. 586. Sen, A., Sherr, C. J., and Todaro, G. J., Phosphorylalian of murine type C viral p12 proteins regulates their extent of binding to the homologous viral RNA, Co//, 10, 489, 1977. 587. Sen, A. and Todaro, G. J., The genome-associated, specific RNA binding proteins of avian and mammalian type C viruses, Cell, 10, 91, 1977. 588. Shank, P. R., Hughes, S. H., Kung, H.-J., Majors, J. E., Quintten, N., Guntaka, R. V., Bishop, J. M., and Varmus, H. E., Mapping unintegrated avian sarcoma virus DNA: termini of linear DNA bear 300 nucleotides present once or twice in two species of circular DNA, Cell, 15, 1383, 1978. 589. Shank, P. R. and Varmus, H. E., Virus-speciflc DNA in the cytoplasm of avian sarcoma virusinfected ceils is a precursor to covalently closed circular viral DNA in the nucleus, J. Viral., 25, 104, 1978. 590. Shanmugam, G., Rapid metabolism of Moloney leukemia virus precursor polypeptides in vlrus infected Swiss mouse embryo cells, Biochem. Biophys. Res. Commun., 78, 517, 1977. 591. Shanmugam, G., Bhadud, S., and Green, M., The virus-specific RNA species in free and membranebound polyribosomes of transformed cells replicating murlne sarcoma-leukemia viruses, Bioehem. Biophys. Res. Commun., 56,697, 1974. 592. Shapiro, S. Z., Strand, M., and August, J. T., High molecular weight precursor polypeptides to structural proteins of Rauscher murlne leukemia virus, J. Mol. Biol., 107,459, 1976. 593. Sheiness, D. and Bishop, J. M., DNA and RNA from uninfected vertebrate cells contain nucleotide sequences related to the putative transforming gone of avian myelocytomatosis virus, J. Virol., 31, 514, 1979. 594. Shen-Ong, G. L. C., Potter, M., Mushinski, J. F., Lavu, S., and Reddy, E. P., Activation of the cmyb locus by viral insertional mutagenesls in plasmaeytoid [ymphosarcomas, 5c'ience, 226, 1077, 1984. 595. Shibuya, T. end Mak, T. W., Host control of susceptibility to erythroleukemia and to the types of leukemia induced by Friend murine leukemia virus: initial and late stages, Cell, 31,483, 1982. 596. Shibuyn, T. and Mak, T. W., A host gone controlling early anaemia or polycythaemia induced by Friend erythroleukaemia virus, Nature (London), 296, 577, 1982. 597. Shibuya, T., Niho, Y., and Mak, T. W., Erythroleukemia induction by Friend leukemia virus: a host gone locus controlling early anemia or polycythemia and the rate of proliferation of late erythroid cells, J. Exp. Mad., 156, 398, 1982. 598. Shields, A., Goff, S., Paskind, M., Otto, G., and Baltimore, D., Structure of the Abelson murine leukemia virus genome, Cell, 18, 955, 1979. 599. Shih, T. Y., Weeks, M. O., Troalet, D. H., Coffin, J, M., and Scolnick, E. M,, Mapping host rangespecific oligonucleotides within genomes of the ecotropic and mink cell focus-inducing strains of Motoney routine leukemia virus, J. Virol., 26, 71, 1978. 600. Shilo, B.-Z. and Weinberg, R. A., DNA sequences homologous to vertebrate oncogenes arc conserved in Drosophila melanogaster, Pror Natl. Acad. Sci. U.S.A., 78, 6789, 1981. 601. Shimotohno, K., Mizutani, S., and Temin, H. M., Sequence of retrovirus provirus resembles that of bacterial transposable elements, Nature (London), 285, 550, 1980. 602. Shimc,tohno, K. and Temin, H. M., No apparent nucleotlde sequence specificity in cellular DNA juxtaposed to retrovirus provlruses, Proc. Natl. Acad, SoL U.S.A., 77, 7357, 1980. 603. Shine, J., Czernilofsky, A. P., Friedrieh, R., Bishop, J. M., and Goodman, H. M,, Nucleotlde sequence at the 5' terminus of the avian sarcoma virus genome, Proc. Natl. Acad. Sci. U,S.A., 74, 1473, 1977. 604. Shinnick, T. M., Lerner, R. A., and Sntclilfe, J. G., Nucleofide sequence Of Moloney routine leukaemla virus, Nature (London),293,543, 1981. 605. Shoemaker, C., Goff, S., Gilboa, E., Paskind, M., Mitra, S. W., and Baltimore, D., Structure of a cloned circular Moloney routine leukemia virus molecule containing an inverted segment: implications for retrovirus integration, Pror Natl. Acad, SoL U.S,A., 77, 3932, 1980. "006. Siden, E. 3 , Baltimore, D., Clark, D., and Rosenberg, N., Immunoglobulin synthesis by lymphoid cells transformed in vitro by Abelson routine leukemia virus, Cell, 16, 389, 1979.

V o l u m e 5, Issue 3

317

607. Siegert, W., Konings, R. N. H., Bauer, H,, and Hofschneider, P, H., Translation of avian myeloblastosis virus RNA in a cell-free ]ysate of Escherichla cot/, Prou. Natl. Acad. ScL U.S.A., 69, 888, 1972, 608. Siegler, R., Zajdel, S., and Lane, I,, Pathogenesis of Abelson-virus-induced murlne leukemia, J. NatL Cancer Inst.,48, 189, 1972. 609. Silverstone, A. E., Rosenberg, N., Baltimore, D., Sato, V. L., Scheid, M. P., and Boyse, E. A., Correlating terminal deoxynucleotidyl transferase and cell.surface markers in the pathway of lymphocyte ontogeny, Cold Spring Harbor Conf. Cell Proliferation, 5, 433, 1978. 610. Sklar, M. D., Shevach, E. M., Green, I., and Potter, M., Transplantation and preliminary characterisat/on of lymphocyte surface markers of Abelson virus.induced lymphomas, Nature (London), 253,550, 1975. 611. Sklar, M. D., White, B. J., and Rowe, W. P., Initiation of oncogenic transformation of mouse lymphocytes in vitro by Abelson leukemia virus, Proc. Natl. Aead. gel U.S.A., 71, 4077, 1974. 612. Soule, H. D. and Arnold, W. J., Marine myeloprolif,;rative virus in ceil culture, J. Natl. Cancer Inst., 45, 253, 1970. 613. Sonza, L. M., Strommer, J. N., HiUyard, R. L., Komaromy, M. C., and Baluda, M. A., Cellular sequences are present in the presumptive avian mycloblastosis virus genome, Proc. Natl. Acid. Sci. U.S.A.,77, 5177, 1980. 614. Spector, D. H., Baker, B., Varmus, H. E., and Bishop, J, M., Characteristics of cellular RNA related to the transforming gene of avian sarcoma viruses, Cell, 13,381, 1978. 615. Spector, D. H., Smith, K., Padgett, T., McCombe, P., Roulland-Dussoix, D., Moscovici, C., Varmus, H. E., and Bishop, J. M., Uninfected avian cells contain RNA related to the transforming gene of avian sarcoma viruses, Cell, 13,371, 1978. 616. Spector, D. H., Varmus, H. E., and Bishop, J. M., Nucleotide sequences related to the transforming gene of avian sarcoma virus are present in the DNA of uninfected vertebrates, Proc. Natl. Acad. Sci. U.S.A., 75, 4102, 1978. 617. Spiegelman, S., Burny, A., Das, M. R., Keydar, J., Schlom, J., Tr&vni'd'ek,M., and Watson, K., Synthetic DNA-RNA hybrids and RNA-RNA duplexes as templates for the pnlymerases of the oncogenic RNA viruses, Nature (London), 228,430, 1970. 618. Spira, J., Babonits, M., Wiener, F., Ohno, S., Wirschubski, Z., Haran-Ghera, N., and Klein, G., Nonrandom chromosomal changes in Thy-l-posltlve and Thy-l-negative lymphomas induced by 7,12dimethylbenzan-thracene in SJL mice, Cancer Res.,40, 2609, 1980. 619. Spira, J., Wiener, F., Ohno, S., and Klein, G., Is trisomy cause or consequence of marine T cell leukemia development? Studies on Robertsonion translocation mice, Proc. Nat/. Acad. Sci. U.S.A., 76, 6619, 1979. 620. Spriggs, D. R., Diebold, M. A., and Kruegec, R. G., BALB/c myeloma retroviruses have mink cell focus-inducing activity, J. ViroL, 36, 541, 1980. 621. Spriggs, D. R. and Krueger, R. G., Envelope proteins of the BALB/c myeloma mink ceil focusinducing (MCF) viruses, Virology, 108,474, 1981. 622. Stacey, D. W., Allfrey, V. G., and Hanafusa, H., Microinjection analysis of envelope-glycoprotein messenger activities of avian leukosis viral RNAs, Proc. Nat/. Acad. Sci. U.S.A., 74, 1614, 1977. 623. Stansly, P. G. and Soule, H. D., Transplantation and cell-free transmission of a reticulum-cell sarcoma in BALB/c mice, J. Nat/. Cancer Inst., 29, 1083, 1962. 624. Staskos, K. A., Collett, M. S., and Farus, A. J., Initiation of DNA synthesis by the avian oncornavirus RNA-direeted DNA polymeruse: structural and functional localization of the major species of primer RNA on the oncornavirus genome, Virology, 71,162, 1976. 625. Steevee, R. A., Spleen focus-forming virus in Friend and Rauscher leukemia virus preparations, J. Natl. Cancer Inst., 54, 289, 1975. 626. Stecves, R. A., Bennett, M., Mirund, E. A., and Cadkowicz, G., Genetic control by the Wlocus of susceptibility to (Friend) spleen focus-forming virus, Nature (London), 218, 372, 1968. 627. Steeves, R. A. and Eckner, R. J., Host-induced changes in infectivity of Friend spleen focus-forming virus, .f. Natl. Cancerlnst.,44, 587, 1970. 628. Steeves, R. A., Eckner, R. J., Bennett, M., Mirand, E. A., and Trudel, P. J., Isolation and characterization of a lymphatic leukemia virus in the Friend virus complex, I. Natl. Cancer Inst., 46, 1209, 1971. 629. Steffen, D., Proviruses are adjacent to c-myc in some murine leukemia virus-induced lymphvmas, Proc. Natl. Acad. SoL U.S.A., 81, 2097, 1984. 630. Steffan, D. and Weinberg, R. A., The integrated grnome of murlne leukemia virus, Cell, 15, 1003, 1978. 63 I. Stehelin, D., Guntaka, R. V., Varmus, H. E., and Bishop, J, M., Purification of cDNA complementary to nucleotide sequences required for neoplastic transformation of fibroblasts by avian sarcoma viruses, J. Mol. Biol., 101,349, 1976.

318

C R C Critical Reviews in O n t o l o g y ~ H e m a t o l o g y

632. Stehetin, D,, Varmus, H. E., Bishop, J. M., and Vogt, P, K,, DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA, Nature (LondoM, 260, 170, 1976. 633. Steinheider, G., Seidel, H, J,, and Kreja, L., Comparison of the biological effects of anemia inducing and poiycythemia inducing Friend virus complex, Experlentia, 35, 1173, 1979. 634. Stephenson, J. R. and Aaronson, S. A., A genetic locus for inducibility of C-type virus in BALB/c cells: the effet:t of a nonlinked regulatory gene on detection of virus after chemical activation, Prec. Natl. Acud. Sci. U.S.A.,69, 2798, 1972. 635. Stephenson, J. R. and Aaronson, S. A., Segregation of loci for C-type virus induction in strains of mice with high and low incidence of leukemia, Science, 180, S65, 1973. 636. Stephenson, J. R. and Aaronson, S. A., Induction of an endogenous B-tropic type C RNA virus from SWR/J mouse embryo cells in tissue culture, Virology, 70, 352, 1976. 637. Stephenson, J. R., Tronit:k, S. R., and Aaronson, S. A., Murine leukemia virus mutants with temperature-sensitive defects in precursor polypeptide cleavage, Cell, 6,543, 1975. 638. Stephenson, M. L., Scott, J. F., and Zamecnik, P. C., Evidence that the'poiyadeny[ic acid segmem of "35S" RNA of avian myeloblastosis virus is located at the 3'-OH terminus, Blot:hem. Biophys. Res. Commun., 55, S, 1973. 639. Stockert, E., O'Donnell, P. V., Obata, Y., and Old, L. J., Inhibition of AKR ]r by SMX-I, a dualtropic marine leukemia :,'irus, Prec. Natl. Acad. $ci. U.S.A., 77, 3720, 1980. 640. Stoll, E., Billeter, M. A., Palmenberg, A., and Weissmann, C., Avian myeloblastosis virus RNA is terminally redundant: implications for the mechanism of retrovirus replication, Cell, 12, 57, 1977. 641. Stoitzfus, C. M. and Dimot:k, K., Evidence for methylation of B77 avian sarcoma virus genuine RNA subunits, 2. Virol., 18,586, 1976. 642. Stoltzfus, C. M. and Kuhnert, L. K., Evidence for the identity of shared 5'-terminal sequences between genuine RNA and subgenomit: mRNA's of B77 avian sarcoma virus, J. ViroL, 32, 536, 1979. 643. Sutcliffe, J. G., Shinnick, T. M., Green, N., Liu, F.-T., Niman, H. L., and Lemur, R. A., Chemical synthesis of a polypeptide predicted from nut:leotide sequence allows detection of a new retroviral gene product, Nature (London), 287, 801, 1980. 644. Sutcliffe, J. G., Shinnit:k, T. M., Verma, I. M., and Lerner, R. A., Nueleotide sequence of Moloney leukemia virus: Y end reveals details of replication, analogy to bacterial transposons, and an unexpected 8ene, Prec. Nell. Acad. ScL U.S.A., 77, 3302, |980. 645. Suzuki, S., FV-4: a new gene affecting the splenomegaly induction by Friend leukemia virus, Jpn. J. Exp. Mud., 45,467, 1975. 646. Suzuki, S. and Axelrad, A. A., Fv-21ocus co~trols the proportion of erythropoietic progenitor cells (BFU-E) synthesizing DNA in normal mice, Cell, 19, 225, 19S0. 647. Suzuki, S. and Matsubara. S., isolation of Friend'leukemia virus resistant line from non-inbred mouse colony, Jpn. J. Exp. Mud., 45,467, 1975. 648. Sveda, M. M. and Soeiro, R., Host restriction of Friend leukemia virus: synthesis and integration of the provirus, Prec. Natl. Acad. Sci. U.S.A., 73, 2356, 1976. 649. Svohoda, J., HIozanek, I., and Much, O., Detection of chicken sarcoma virus after trausfection of chicken fibroblasts with DNA isolated from mammalian cells transformed with gous virus, Folla Biol., IS, 149, 1972. 650. Svoboda, J., Hlozanek, I., Much, O., Mit:hlova, A., Riman, J., and Urbankova, M., Transfection of chicken fibroblasts with single exposure to DNA from virogenic mammalian cells, J. Gun. Virol, 21~ 47, 1973. 65i. Swanstrom, R., DeLorbe, W. J., Bishop, J. M., and Varmus, H. E., Nucleotide sequence of cloned unintegrated avian sarcoma virus DNA: viral DNA contains direct and inverted repeats similar to those in transposable elements, Prec. Natl. Acad. Sci. U.S.A., 78, 124, 1981. 652. Swanstrom, R., Varmus, H. E., and Bishop, J. M., Nucleotide:sequence of the 5' noncodlng region and part of the gaggene of Runs sarcoma virus, J. Virol., 41,535, 1982. 653. Tel, J., Kung, H.-J., Varmus, H. E., and Bishop, J. M., Characterization of DNA complementary to nut:leotide sequences adjacent to poly(A) at the 3'-terminus of the avian sarcoma virus genuine, Virology, 79, 183, 1977. 654. Tambourin, P. E., Wendling, F., Jasmin, C., and Smadja-Joffe, F., The physiopathology of Friend leukemia, Leuk. Res., 3, 117, 1f79. 655. Tambourin, P., Wendling, F., and Mortau-Gachelin, F., Friend leukemia as a multiple-step disease,' Blood Ceils, 7, 133, 19Sl. 656. Taylor, J. M., An analysis of the role of tRNA species as primers for the transcription into DNA of RNA tumor virus genomes, Bir Biophys. Acta, 473, 57, 1977. 657. Taylor, J. M., DNA intermr of avian RNA tumor viruses, Curt. Too.-Mierobiol. Immunol., 87, 23,1979. 658. Taylor, J. M., Cordell-Stewart, B,, Rohde, W., Goodman, H. M,, and Bishop, J. M., Reassociation of 4 S and 5 S RNA's with the genome of avian sarcoma virus, Virology, 65, 248, 1975.

V o l u m e 5, Issue 3

:]19

659, Taylor, J, M. and lllmensee, R,, Site on the RNA of an avian sarcoma virus at which primer is bound) J. Virol,, 16, 553, 1975. 660. Teich, N. M. and Dexter, T. M., Effects of merino leukemia virus infection on differentiation of hematopoietic cells in vitro, Cold Spring Harbor Coal Cell Proliferation, 5,657,1978. 66I. Temin, H. M., The effects of actinomycin D on growth of Rous sarcoma virus ~n vitro, VirotoBy, 20, 577, 1963. 662. Temin, H. M., The DNA provirus hypothesis: the establishment and implications of RNA.directed DNA synthesis, Science, 192, 1075, I976. 663. Temin, H. M. and Mizutani, S,, RNA-dependent DNA polymerase in virions of Rous sarcoma virus, Nature (London), 226, I211, 1970. 664. Tennant, J, R., Derivation of a murine lymphoid leukemia virus, J. Nat1, Cancer Inst., 28, 1291, I962. 665. Tennant, R. W., Otten, J. A., Brown, A., Yang, W. K,, and Kennel, S. J., Characterization of Fv-i host range strains of murine retroviruses by titration and p30 protein characteristics, Virology, 99, 349, 1979. 666. Thomas, C. Y. and Coffin, J, M., Genetic alterations of R]'IA leukemia viruses associated with the development of spontaneous thymic leukemia in AKR/J mice, J. Virol,, 43,416, 1982. 667. Thomas, C. Y., Khiroya, R., Schwartz, R. S., and Coffin, J. M., Role of ~ecombinant ecotropic~and pGly~ropic viruses in the development of spontaneous thymic lymphomas ~n HRS/J mice, J. Virof., 50, 397, 1984. 668. Thomason, A. R., Brian, D. A., Velicer, L. F., and Rottman, F. M., Methylation of high-molecularweight subunit RNA of feline leukemia virus, J, Virol., 20, 123, t976. 669. Tronick, S. R., Robbins, K. C., Canaani, E., Devare, S, G., Anderson, P, R., and Aaronson, S. A., Molecular cloning of Moloney murine sarcoma virus: arrangement of vlrus-related sequences within the normal mouse genome, Proc. Natl. Acad. Sci. U,S.A., 76, 6314, 1979. 670. Tronick, S. R., Scolnick, E. M., and Parks, W. P., Reversible inactivation of the deoxyribonucleic acid polymerase of Rauscher leukemia virus, J. Virol.,.lO. 885, 1972, 671. Troxler, D. H., Boyars, J. K., Parks, W. P., and Scolnick, E. M., Friend strain of spleen focusforming virus: a recombinant between mouse type C ecotropic viral sequences and sequences related to xenotropic virus, J, Virol,, 22, 361, 1977, 672, Troxler, D. H., Lowy, D,, Howk, R., Young, H., and Scoinick, E. M., Friend strain of spleen focusforming virus is a recombinant between ecotropic mur[ne type C virus and the envgene region of xenotropic type C virus, Proc. Natl. Acad. 5ci. U.S.A.,74, 4671,1977. 673. Troxler, D. H., Parks, W. P,, Vass, W. C,, and Scolnick, E. M., Isolation of a fibroblast nonproducat cell line containing the Friend strain of the spleen focus-forming virus, Virology, 76,602,1977. 674. Troxler, D. H., Ruscetti, S. K,, Linemeyer, D. L., and Seolnick, E. M., Helper-independent and replication defective erythroblastosis-inducing viruses contained within anemia-inducing Friend virus complex (FV-A), Virology, 102, 28, 1980. 675. Troxler, D. H. and Scolnick0 E. M., Rapid leukemia induced by cloned Friend strain of replicating routine type-C virus. Association with induction of xenotropic-rela~ed RNA sequences contained in spleen focus-forming virus, Virology, 85, 17, 1978. 676. Troxler, D. H., Yuan, E., Linemeyer, D., Ruscetti, S., and Sr E. M., Helper-independent mink cell focus-inducing strains of Friend routine type-C virus: potential relationship to the origin of the replication-defective spleen focus-forming virus, J. Exp. Mad., 148, 639,1978. 677. Tsichlis, P. N. and Coffin, J. M., Recombination between the defective component of an acute leukemia virus and Rous associated virus O, an endogenous'virus of chickens, Proc. Natl, Acid. Sci. U.S.A., 76, 3001, I979. 678. Tsichlis, P. N. and Coffin, J. M., Recombinanls between endogenous and exogenous avian tumor viruses: role of the C region and other portions of the genome in the control of replication and transformation, J. Virol.,33,238, 1980. 679. Tsichlis, P. N., Strauss, P. G., and Hu, L. F., A common region for proviral DNA integration in MoMuLV-induced rat thymic lymphomas, Nature (London), 302, 445,1983. 680. Tsuchida, N., Bhaduri, S., Raskas, H. J., and Green, M,, Partial purification of intracellular routine sarcoma-leukemia virus RNA sl~ecies by membrane filtration, lntcrvirology, I, 27, 1973. 681. Tsuchida, N. and G r i n , M., Intr,~cel|ular and virion 35 S RNA species of murine sarcon~a and leukemia viruses, Virology, 59, 258, 1974. 682. Tsuchida, N. and Green, M.I Intracellular viral RNA species in mouse ceils nonproductively transformed by the routine sarcoma virus, J. Virol,, 14, 587, 1974. 683. Tsuchida, N., Robin, M. S., and Green, M,, Viral RNA subunits in cells transformed by RNA tumor viruses, Science, 176, 1418, 1972, 684. Tuns, .L-S., Plnter, A., and Flelssn~r, E., Two species of type C viral core polyproVcin on AKR mou~ leukemia cells, J. Viroi., 23,430, 1977.

320

C R C Critical Reviews in O n c o l o g y / H e m a t o l o g y

685. Tung, J.-S., Yoshiki, T. and Fleissner, E., A core polyproteln of murine leukemia virus on the surface of mouse leukemia ceils, Cell, 9, 573, 1976. 686. Upton, A. C., Wolff, F. F., Furth, J., and Kimball, A. W., A comparison of the induction of myeloid and lymphoid leukemias in X-radiated RF mice, Cancer Res., 18, 842, 1958. 687. Van Beveren, C., Goddard, J. G., Barns, A., and Verma, I. M., Structure of Moloney routine leukemia viral DNA: nueleotide sequence of the 5' long terminal repeat and adjacent cellular sequence, Prec. NatL Acad. Sci. U.S.A., 77, 3307, 1980. 688. Van Beveren, C., Rands, E., Chattopadhyay, S. K., Lowy, D. R., and Verma, 1. M., Long terminal repeat of marine retroviraI DNAs: sequence analysis, host-provlral junctions, and preintegration site, 2. Virol., 41, 541, [982. 689. Van Beveren, C., van Straaten, F., Galleshaw, J. A., and Verma, I. M., Nucleotide sequence of the genome of a murine sarcoma virus, Cell, 27, 97, 1981. 690. van der Putten, H., Quint, W., van Raaij, J., Verma, 1. M., Robanus Maandag, E., and Barns, A., M-MuLV-lnduced leukemogenesis: integration and structure of recombinant proviruses in tumors, Cell, 24, 729, 1981. 691. van de Van, W. J. M., van Zaane, D., Onnekink, C., and Bloemers, H. P. J., Imputed processing of precursor polypeptides of temperature-sensitive mutarns of Ranscher routine leukemia virus, J. Vi. ro1.,25, 553, 1978. 692. Van Griensven, L. J. L. D. and Vogt, M., Rauscher "mink cell focus-inducing" (MCF) virus causes erythroleukemia in mice: its isolation and proper(its, Virology, 101,376, 1980. 693. van Ooyen, A. and Nusse, R., Structure and nucleotide sequence of the putative mammary oncogene Jar-l; proviraI insertions leave the protein-encoding domain intact, Cell, 39, 233, 1984. 694. van Zaane, D., Dekker-Miehielsen, M. J. A., and Bloemers, H. P. J~, Virus-specific precursor polypeptides in cells infected with Rauseber leukemia virus: synthesis, identification, and processing, Virology, 75, 113, 1976. 695. van Zaane, D., Gielkens, A. L. J., Oekker-Michielsen, M. J. A., and Bloemers, H. P. J., Virusspecific precursor polypeptides in cells infected with Rauscher leukemia virus, Virology, 67, 544, 1975. 696. van Zaane, D., Gielkens, A. L. J., Hesselink, W. G., and Bloemers, H. P. J., Identification of Rauscher routine leukemia virus-specific rnRNAs for the synthesis of gag- and env-gene products, Prec. Natl. Acad. $ci. U.S.A., 74, 1855, 1977. 697. Varrnus, H. E., Ountaka, R. V., Dang, C. T., and Bishop, J. M., Synthesis, structure and function of avian sarcoma vlrus-specific DNA in permissive and nonpermissive cells, Cold Spring Harbor Syrup. Quant. Biol., 39, 987, 1974. 698. Varmus, H. E., Guntaka, R. V., Fan, W. J. W., Hsasley, S., and Bishop, J. M., Synthesis of viral DNA in the cytoplasm of duck embryo fihroblasts and in enucleated cells after infection by avian sarcoma virus, Proc. Natl. Acad. Sci. U.S.A., 71, 3874, I974. 699. Varrnus, H. E., Heasley, S., Kung, H.-J., Oppermann, H., Smith, V. C., Bishop, J. M., and Shank, P. R., Kinetics of synthesis, structure and purification of avian sarcoma virus-specific DNA made in the cytoplasm of acutely infected cells, J. Mol. Biol., 120, 55, 1978. 700. Varmus, H. E., Heasley, S., Linn, J., and Wheeler, K., Use of alkaline sucrose gradients in a zonal rotor to detect integrated and unintegrated avian sarcoma virus-specific DNA in cells, J. V#oL, 18, 574, 1976. 701. Yarmus, H. E., Quintrall, N., and Ortiz, S., Retroviruses as mutagens: insertion and excision of a nontransforming provirus alter expression of a resident transforming provirus, Cell, 25, 23, 1981. 702. Varrnus, H. E~.and Shank, P. R., Unintegrated viral DNA is synthesized in the cytoplasm of avian sarcoma virus-transfor~,d duck cells by viral DNA polymerase, .I. Virol., 18, 567, 1976. 703. Varrnus, H. E., Vogt, P. K., and Bishop, J. M., Integration of deoxyribonucleic acid specific for Rous sarcoma virus after infection of permissive and nonpetmissive hosts, Prec. Natl. Acad. Sol. U.S.A., 70, 3067, 1973. 704. Vennstr~m, B. and Bishop, J. M., Isolation and characterization of chicken DNA homologous to the two putative oneogenes of avian erythroblastosis virus, Cell, 28, 135, 1982. 705. Verlrla, I. M., Studies on reverse transcriptase of RNA tumor viruses, ill. Properties of purified Moloney routine leukemia virus DNA polymerase and associated RNase H, d. Virol., 15,843, 1975. 706. Verma, L M., Genome organization of retroviruses. II1. Restriction endonuclease cleavage maps of mouse sarcoma virus double-stranded DNA synthesized in vitro, Nucleic Acids Res., 6, 1863, 1979. 707. Vetma, I. M., Organization and structure of retrovirus genomes, in Replication of Viral and Cellular Gelwmes, Backer, Y., Ed., Martinus Nijhoff, Boston, 1983, 275. 708. Verma, l. M,, Meuth, N. L,, and Baltimore, D., Covalent linkage between ribbnucleic acid primer and deoxyribonucleic acid product of the avian myeloblastosis virus deoxyribonucleic acid polymeruse, J. Virol., I0, 622, 1972.

V o l u m e 5, Issue 3

321

709. Verma, I. M., Meuth, N, L., Bromfeld, E., Manly, K. F., and Baltimore, D., Covalently linked RNA.DNA mdlecule as initial product of RNA tumour virus DNA polymerase, Nal. (London) N. Biot.,233, 131, 1971. 710. Vigier, P, and Gold~, A., Effects of actinomycin D and of mitomycin C on ehe development of Rous ~arcoma virus, Virology, 23, 511, [964. 711. Villemur, R., Rassart, E., DesGroseillers, L., and Jolicoeur, P., Molecular cloning of viral DNA from leukemogenie Gross passage A routine leukemia virus and nucleotide sequ~.nce of its long terminal repeat, J. Viral., 45, 539, 1983. 712. Vogt, M., Properties of "mink cell focus-forming" (MCF) virus isolated from spontaneous lyrephoton lines of BALB/e mice carrying Moloney leukemia virus as an endogenous virus, Virology, 93, 226, 1979, 713. van der Helm, K~ and Duesberg, P. H., Transl~tior~ cf Rous ~arcom~ v~rtts RNA ~n a cell-free system from ascites Krebs 11 cells, Ptoc. Natl. Acad. ScL U.S.A., 72,614, 1975. 714. Wang, L.-H, and Duesb~rg, P., Properties and location of poly(A) in Rous sarcoma virus RNA, J. ,~ Viral., 14, 1515, 1974. 715. Wang, L.-H., Duesberg, P., Beemon, K., and Vogt, P, K., Mapping RNase T,-resi~tant oligonucleotides of avian tumor virus RNAs: sarcoma-specific oligonucleotides are near the poly(A) end and oligonucleotides common to sarcoma and transformation-defective viruses are at the poly(A) end, .L Viral., 16, 1051, 1975. 716. Wan~, L,-H., Duesberg, P. H., Kawai, S., mad Hanafosa, H., Location of eovelope.specific and sarcoma-specific oligonucleotides on RNA or Schmidt.Ruppin Rous sarcoma virus, Proc. Natl. Acad. ScL U.S.A., 73, 447, 1976. 717. Wang, L.-H., Duesberg, P., Mellon, P,, and Vogt, P, K., Distribution of envelope-specific and sarcoma-s~cific nucleotide sequences from different parents in the RNAs of avian tumor virus recombinants, Proc. Naff. Acad. Sci. U.S.A.,73, 1073, 1976. 718. Wang, L.-H., Duesberg, P. H., Robins, T., Y~kota, H., and Vogt, F. K., The termina| oligonucieotides of avian tumor virus RNAs are genetically linked, Virology, 82, 472, 1977. 719. Wang, L..H., Galehouse, D., Mellbn, P., Duesberg, P., Mason, W. S., and Vogt, P. K., Mapping oligonucleotides of Rous sarcoma virus RNA that segregate with polymerase and group-specific antigen markers in recombinants, Proc, Natl. Acad. Sci. U.S.A., 73, 3952, 1976, 720. Ware, L. M. and Axelrad, A. A., Inherited resistance to N- and B-tropic routine leukemia viruses in vitro: evidence that congenic mouse strains SIM and SIM.R differ at the Fv-I locus, Virology, 50, 339, 1972. 721. Weinberg, R. A., ras oncogenes and the molecular mechanisms of carcinogenesis, Blood, 64, 1143, 1984. 722, Weiss, R,, Teich, N., Varmus, H., and Coffin, J., Eds., RNA Tumor Viruses, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1982. 723. Weiss, S. R., Hackett, P, B., Oppr H., Ullrich, A., Levintow, L., and Bishop, J. M., Celltree translation of avian sarcoma virus RNA: suppression of the sag termination codon does not augment synthesis of the joint gag/polproduet, Cetl, 15,607, 1978, 724. Weiss, S. R+, Varmus, H. E., ann Bishop, J. M., The size and genetic composition of virus-specific RNAs in the cytoplasm of cells producing avian sarcoma-leukemia viruses, Cell, 12, 983, 1977. 725. Weiss, S. R., Varmus, H. E+, and Bishop, J. M., Cell-free translation of purified avian sarcoma virus srcmRNA, J. Virot., 110, 476,1981. 726. Weissmann, C., Parsons, J. T,, Coffin, J, M,, Rymo, L,, Billete'., M. A., and Hofstetter, H., Studies on the structure and synthesis of Rous sarcoma virus RNA, Cold Spring Harbor Syrup. Quant. Biol., 39, 1043,1974. 727, Wendling, F., Moreau-Gm:helin, F+, and Tambourin, P., Emergence of tumorigenic cells during the course of Friend virus leukemias, Prod:. Nat/. Acad. $ci. U.S.A., 78, 3614, 1981. 728. Wendling, F., Tambourin, P., Gallien-Lartigue, O., and Charon, Mr, Comparative differentiation and numeration of CFUs from mice infected either by the anemia- or polycythemia-inducing strains of Friend viruses, Int. f. Cancer, 13,454, 1974, 729. Westin, E. H., Wong-Staal, F., Gelmann, B. P., Dalla Favera, R., Papas, T, S., Lautenberger, 2. A., Eva, A., Reddy, E. P., Tronick, $. R., Aaronson, S. A., and Gallo, R. C.. Expression of cellular homologues of retroviraI oncgenes in human hematopoietic cells+ Proc. Natl. Acad, Sci. U.S.A., 79, 2490,1982. 730. Westway, D., Payee, G. and Yarmus, H. E., Proviral ddetions and oncogene base-s0bstitutions in insertionaily mutagenized e-mYc atleles may contribute to the progression of avian bursal tumors, Pror Natl. Acad. Sci. U,S.A., 81,843,1984. 731. Wiener, F., Ohno, S., Spira, J., Haran-Ohera, N., and Klein, G+, Cytogenetic meppinli of the trisomic segment of chromosome 15 in tour/he T-cell leukaemia, Nature (London), 275,658,1978.

322

C R C Critical R e v i e w s in O n c o t o g y / H e r a a t o l o g y

732. Wiener, F., Ohno, S,, Spira, J., Haran-Ghera, N., and Klein, G., Chromosome changes (trisomics #15 and 17) associated with tumor progression in leukemias induced by radiation leukemia virus, J. Natl. Cancer Inst., 61,227, 1978~ 733. Wiener, F., Spira, 2., BaboMts, M., Haran.Ohera, N., and Klein, G., Non-random duplication of chromosome I5 in routine T-cell leukemias: further studies on translocation heterozygotes, Int. J. Cancer, 26, 661, 1980. 734. Wiener, F., Spira, J., Ohno, S., Haran-Ghera, N., and Klein, O., Chromosome changes (trisomy 15) in routine T-cell leukemia induced by 7,12-dimethylbenz(a)anthracene (DMBA), Int. J. Cancer, 22, 447, 1978. 735. Witte, O. N. and Baltimore, D., Relationship of retrovirus polyprotck, cleavages to viriert maturation studied with temperature-sensitive murine leukemia virus mutants, I. tirol., 26,750, 1978. 736. Witte, O. N., Dasgupta, A., ar:d Baltimore, D., Abelsort raurir~e ieukaemi~ viru~ protein ~s phosphorylated in vitro to form phosphotyrosine, Nattlre (London), 283, 826, 1980. 737. Witte, O. N., Golf, S., Rosenberg, N., and Baltimore, D., A transformation-defective mutant oI Abelson murine leukemia virus lacks protein kinase activity, Proc. Natl, Acad. $ci. U.S.A., 77, 4993, 1980. 738. Witte, O. N., Rosenberg, N., Paskind, M., Shields, A., and Baltimore, D., Identification of an Abelson murine leukemia virus-encoded protei~ presen.t in transformed fibrobiast and lymphoid cells, Proc. Nat]. Acad. SoL U.S.A., 75, 2488, 1978. 739. Witte, O, N,, Tsukamoto-Adey, A., and Weissman, I. L., Cellular maturation of oncornavirus glycoproteins: topological arrangement of precursor and product forms in cellular membranes, Virot. ogy, 76, 539, 1977. 7,10. Witte, O. N. and Weissman, 1. L., Polypeptides of Moloney sarcoma-leukemia virions: their reseiulion and irxcorporation into extraceIIt~lar virions, Vir~togy,6l, 575, t974. 7,tl. Witte, O. N. and Weissman, I. L., Oncornavirus budding: kinetics of formation and utilization of viral membrane glycoprotein, Virology, 69,464, I976. 742. WiRe, O. N. and Wirth, D. F., Structure of the routine leukemia virus envelope glycoprotein precursor, J. Virol., 29,735, 1979, 743. Wolff, L., Hubbert, N., and Ruscetti, S., Structural analysis of the spleen focus-forming virus envelope gene product, Virology, 133,376,198,t. 744. Wolff, L., Kaminchik, J., Hankirts, W. D., arm Ruscetti, S. K., Sequence comparisons of the anemiaand polycythemia-inducing strains o1 Friend spleen focus-forming virus, J. Virol., 53,570, 1985. 745. Wolff, L., Koller, R., and Ruscetti, S., Monoclonal antibody to spleen focus-forming virus-encoded gp~2 provides probe for the amino-terminal region of retrovirai envetope proteins that confers dual tropism and xenotropism, J. Virol., 43, 472,1982. 746. Wolff, L., Scolnick, E., and Rtiscetti, S., Ertvelope gene of the Frier~d spleen focus-forming virus: deletion and insertions in the 3' gp70/pl$~-encoding region have resulted in unique features in the primary structure of its protein product, Peon. Natl. Acad, Sci. U.S.A., 80, 4718, 1983. 747. Wong, T. C. and Lai, M. M. C., Avian reticuloendotheliosis virus contains a new class of oncogene of turkey origin, Virology, 111,289,1981. 748. Woolley, G. W. and Peters, B. A., Prolongation of life in high-leukemia AKR mice by cortisone, Froc. Soc. Exp. Biol. &fed., 82, 286, 1953. 749. Yamamoto, T., de Crombrugghe, B., and Pastan, I., ld&tification of a functional promoter in the long terminal repeat of Rous sarcoma virus, Cell, 22,787, 1980. 750. Yamamoto, T., Jay, G., and Pastan, I., Unusual features in the nucteotide sequence of a eDNA clone derived from'the common region of avian sarcoma virus messenger RNA, Proc. Natl. Acad. Sci. U.S.A.,77, 176, 1980. 751. Yang, W. K., Kiggans, .l, O., Yang, D.-M., Ou, C.-Y., Tennant, R. W., Brown, A., anti Bassin, R. H., Synthesis and clrcularization of N- and B-tropic retroviraI DNAin Fv-I permissive and restrictive mouse cells, Proc. Natl. Acad. Sci. U.S.A., 77, 2994, 1980. 752, Yang, W. K., Yang, D.-M.,and Kiggans, .t O., Jr., Covalently closed circular DNAs of routine type C retroviruses: depressed formation in cells treated with cycloheximide early after infection, J. ViroI., 36, 181, 1980. 753. Yeger, H., Kalnins, V. I., and Steph9 J. R., Type-C retrovirus maturation and assembly: posttranslational cleavage of the gsg-gene coded precursor polypeptidc occurs at the cell membrane, Virology, 89, 34, 1978. 754. Yoshida, M., Kawai, S., and Toyoshima, K., Uninfected e,vian cells contain structurally unrelated progenitors of viral sarcoma genes, Nature (London), 287,653, 1980. 755. Yoshida, M. and Yoshikura, H., Analysis of spleen focus-forming vtrus-speclfiC RNA sequences coding for spleen focus-fo~ming virus-slmcific glyc0protein wi~h a mofecuIar weight of 55,000(gp5~), J. ViroL, 33,587, 1980. .

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756. Yoshlmura, F. K, and Weinberg, R. A,, Restriction endonuclease cleavage of linear and closed circular routine Ieukemia viral DNAs: discovery of a smaller circular form, Cell, 16,323, 1979. 757. Yoshinaka, Y. and Loftig, R. B., Properties of a P70 proteolytie factor of murine leukemia viruses, Cell, 12, 709, 1977.