Established leukemia cell lines: Their role in the understanding and control of leukemia proliferation

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E S T A B L I S H E D L E U K E M I A CELL LINES: T H E I R ROLE IN T H E U N D E R S T A N D I N G AND C O N T R O L OF L E U K E M I A P R O L I F E R A T I O N Author:

Motoo Hozumi Department of Chemotherapy Saitama Cancer Center Research Institute Inn, Saitama, Japan Dot~ald, Metcalf Cancer Research Unit Walter and Eliza Hall Inslitute Melbourne, Victoria, Australia

I. I N T R O D U C T I O N The mechanisms of leukemogenesis and autonomous proliferation of leukemia cells are still unknown. For investigation of these mechanisms and control of proliferation of leukemia cells, various cell lines with the characteristics of cells at different stages of leukemic development have been established. It has been shown that normal bone marrow hematopoietic progenitor cells can be cultured in vitro for a long time in the presence of certain growth factors, t.' and studies have been made on changes in the control of growth and differentiation of these progenitor cells in culture during leukemogenic transformation. 3-Js The first part of this review describes recent studies on the mechanisms of these changes. Numerous human |eukemia-lymphoma cell lines have been obtained since the first establishment of a human B-lymphoid cell line (Rail) from a biopsy specimen of an African Burkitt tumor. 36-st Although these cell lines show heterogeneity in various markers, the results of studies on multiple markers of ieukemia-lymphoma cell lines suggest that each cell line can be assigned to a particular stage of lymphoid, myeloid, or erythroid differentiation of a single pluripotent stem cell and that the heterogeneity of the leukemia cell lines reflects different patterns of normal hematopoietic cell differentiation. 3a.39The growth and differentiation of various myeloid leukemia cell lines from both humans and experimental animals and those of some human lymphoid leukemia cell lines have been found to be affected by various compounds, s2-22~These results suggest that tile mechanisms of leukemogenesis of some leukemia ceils involve impairment of differentiation in the normal hematopoietic process. Although induction of differentiation of leukemia ceils has mainly been investigated with myeloid leukemia cell lines from experimental animals and leukemic patients, s2-'" induction of differentiation of several human lymphoid leukemia cell lines into nlature lymphoid cells has also recently been demonstrated, t6s'7' Furthermore, primary cultures of fresh leukemic cells from patients with various types of leukemia were induced to differentiate into mature cells by several inducers of differentiation of established leukemia cell lines. 2~t-236 During studies on induction of differentiation of these leukemia cells, various types of compounds, including both physiological and nonphysiological compounds, were found to affect induction of differentiation. 52 "256 Recent analysis of various mechanisms of induction of differentiation of myeloid leukemia cell lines 53-61'ag-9'.9~.94.133,'"-2'j showed that the expressions of several oncogenes are suppressed during induction of differentiation of leukemia cells, suggesting that control of expression of oncogenes is involved in the mechanisms of differentiation of leukemia cells as well as those of leukemogenesis. "'=~

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On the basis of these findings on in vitro induction of differentiation of leukemia cells, the effects of various compounds on in vivo induction of differentiation of some murine myeloid leukemia cell lines, such as MI cells, were e• s''''-'.''4-22~ Results showed that some compounds with activity to induce differentiation of leukemia cells in vitro were also effective in vivo. It was also found that in vivo induction of differentiation of leukemic cells had therapeutic implications, since the survival of animals inoculated with leukemia cells was prolonged markedly by in vivo induction of terminal differentiation of these cells. ~''s's''2t'2a~ Furthermore, some therapeutic improvements in patients with myeloid leukemia were observed on administration of various inducers of in vitro differentiation of human myeloid leukemia cell lines. 2J'-2'6 This paper describes these studies on in vivo induction of differentiation of leukemia cells and their implications in treatment of leukemia. II. E S T A B L I S H M E N T OF P R E L E U K E M I C H E M A T O P O I E T I C P R O G E N I T O R C E L L LINES AND G R O W T H F A C T O R - D E P E N D E N T LEUKEMIA CELL LINES Recent studies showed that bone marrow hematopoietic progenitor cells from various animals could be cultured in vitro for a long period in certain culture conditions. ''a Several ~nurine hematopoietic progenitor cell lines that proliferate in vitro in the presence or absence of specific growth factors have also been established. AlthOugh most growth factor-dependent cell lines had no leukemogenicity in syngeneic animals, some growth factor-independent cell lines, that were formed either spontaneously or by treatment with carcinogens such as virus or chemical carcinogens, had a leukemogenic potential. These hematopoietic progenitor cell lines that can grow for a long time, or even indefinitely, in vitro in the presence or absence of specific growth factors are useful for studies on the mechanisms of leukemogenesis and the regulation of growth and differentiation of preleukemic and leukemic cells. The mechanisms of progressive and unrestrained growth of leukemic cells are unclear, but leukemogenic processes in murine hematopoietic progenitor cells were postulated to occur at least in three stages: (1) immortalization of growtfi factor-dependent hematopoietic progenitor cells; (2) autonomy and leukemogenesis through the autogenous production of growth factor; and (3) acquisition of in vivo leukemogenicity. 3'~3 There is still no unequivocal evidence that immortality is not a normal property of hematopoietic progenitor cells, since some pluripotential hematopoietic stem cell~ may have this property. However, the immortality of growth factor-dependent lines is reported to be an abnormal state since such lines invariably showed gross karyotypic abnormalities. 3 On the other hand, activations of multiple oncogenes have recently been postulated to be involved in carcinogenic processes, and the activations of several oncogenes such as myc, the adenovirus EIA gene, and large T (for tumor antigen) of polyoma virus have been found to be required to immortalize primary cells in culture. 4-7 These findings suggest that immortalization of the hematopoietir progenitor ce!ls is involved in mechanisms of the early stage of leukemogenesis and that the establishment and characterization of immortalized cell lines are valuable for understanding the mechanisms of leukemogenesis and those in preleukemic cells. For autonomous growth, which is one of the most prominent characteristics of tumor cells, some hematopoietic progenitor cells in early phases of leukemogenic proce,~:ses have been found to secrete certain growth factors for their own growth in the m,.'dium. The production and action of growth factors may be involved in the mechanisms of leukemogenic processes of hematopoietic progenitor cells. These processes can be analyzed in certain cultured hematopoietic progenitor cell lines or leukemia cell

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lines producing the growth factors, such as in p cell~." and T-lymphoid leukemia cell lines. ,,~o The final phase of leukemia development may be the acquisition of autonomous proliferation both in vitro and in vivo. Among various established leukemia cell lines, some leukemia cell lines have been shown to be useful for investigations of the certain phases of leukemia development. On the other hand, many established nonlymphoid leukemia cell lines have been suggested to show phenotypic properties of hematopoietic stem cells in certain stages of maturation. The properties of these established hematopoietic progenitor cell lines in the early phase of leukemogenesis are described in this paper. A. Growth Factor-Dependent Preleukemic Hematopoietic Progenitor Cell Lines The method for long-term culture of murine bone marrow hematopoietic progenitor cells described by Dexter et al. j and modified by Greenberger 2 is useful for establishmerit of preleukemic hematopoietic progenitor cell lines that proliferate indefinitely in the presence of certain growth factor. These progenitor cell lines have been found to have multipotential (B6SutA and Rocl3-1) ~' or bi- or monopotential (FDC-P, BM-1, P, and other undesignated cell lines) 8.'2-'s hematopoietic stem cell properties producing T lymphocytes, B lymphocytes, neutrophilic granulocytes, basophilic granulocytes, mast cells, eosinophilic granulocytes, erythroid cells, and megakaryocytes. Some progenitor cell lines are multipotential with the capacity for differentiation of erythroid, neutrophil, eosinophil, basophil, and mast cell types, whereas other cell lines 8,'~-~a are committed to only one or two cell types. However, no pluripotential stem cell lines that can reconstitute total hematopoiesis in vivo have yet been obtained, t9 Although the growth factors for each cell lineage of the hematopoietic progenitors remai.n to be investigated, proliferation of many progenitor cell lines has been shown to depend on interleukin 3 (IL-3) found in the conditioned medium (CM) of the mouse monocytic leukemia cell line WEHI-3. 8.1~-~9 These hematopoietic cell lines require a constant source of IL-3 and begin to die within 6 hr after removal of the source of this growth factor, t9 Furthermore, it has been reported that derivation of growth factorindependent variants of the growth factor-dependent cell lines from continuous suspension cultures is rare. 2~ Growth of some hematopoietic progenitor cell lines is dependent on other growth factors, such as interleukin 2 (IL-2), mast cell growth factor (MCGF), B-cell growth factor (BCGF), colony-stimulating factor (CSF), and P cellstimulating factor (PSF). ~.tt'19 lhle et al. ~' recently purified 11.-3 to homogeneity from CM of WEI-II-3 cells. This purified 1L-3 had an apparent molecular weight of 28,000, as observed in previous studies on IL-3. With this purified IL-3 preparation, they demonstrated that in addition to its 20-a,-hydroxysteroid dehydrogenase-inducing activity in cultures of nu/nu mouse splenic lymphocytes, IL-3 had growth factor activity in WEHI-3 cells and MCGF, PSF, and CSF activities, although the CSF activity of IL-3 constituted only a small percentage of the total CSF activity found in the CM of concanavalin A (Con A)-stimulated lymphocytes. These findings suggest that IL-3 plays an important role in regulation of proliferation of various hematopoietic progenitor cells. It is unknown, however, whether the predominance of IL-3-dependent lines is due to the culture conditions used to obtain the cell lines, or to 1L-3 being one of the major growth factors for stem cells. More growth factor-dependent hematopoietic progenitor ceil lines are derived from bone marrow cultures infected with RNA type C viruses (retroviruses) than from uninfected cultures. Compared with progenitor cell lines from uninfected cultures, those derived from retrovirus-infeeted cultures show an earlier stage of maturation arrest in the sequence of development of hematopoietic stem cells and a higher incidence of

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multipotential hematopoietic cell lines. '1.~~ However, growth factor-dependent cell lines derived from virus-infected continuous mouse bone marrow cultures do not necessarily release infectious virus, nor do they contain viral-specific RNA or structural proteins. 12.~7Therefore, some hematopoietic progenitor cell lines may have been derived from uninfected hematopoietic stem cells or may have been infected but lost viral genes during long-term in vitro culture. Although unlimited self renewal of hematopoietic progenitor cells with growth factor, IL-3, did not necessarily require retrovirus infection, most hematopoietic progenitor cell lines from uninfected cultures were not leukemogenic. 19 After their injection into adult or newborn mice, the growth factor-dependent hematopoietic progenitor cell lines derived from some virus-infected bone marrow cultures produced myeloid leukemia, a disease distinct from that caused by the primary infecting viruses in cultures of the progenitor cells. ~2 B. Growth Factor-lndependent Hemat0Poietic Progenitor Cell Lines

It has recently been reported that some growth factor-independent variant hernatopoietic progenitor cell lines emerge from growth factor-dependent progenitor cell lines. Schrader and CrappeP found that such growth factor-independent variant cell lines appeared from a PSF-dependent mouse bone marrow hematopoietic cell line, P. This variant cell line had concomitantly acquired the capacities for autonomous growth in the absence of exogenous PSF and for autogenous production of PSF. Furthermore, the variant cells absorbed PSF and, in some culture conditions, responded to exogenous PSF, suggesting a link between the two newly acquired properties of the ceils. Unlike the parental PSF-dependent cells, the autonomous variant cell lines tested formed progressively growing tumors in syngeneic mice and the autogenous production of PSF appeared to act as a mechanism for malignant transformation of bone marrow hematopoietic progenitor cells. Although the autonomous variant P cells had the capacities for autonomous growth and autogenous production of PSF, they still responded to exogenous sources of PSF, especially when plated at relatively low density in agar. On the other hand, Schrader and CrappeP proposed that mouse myelomonocytic leukemia WEH1-3B cells that produced PSF arose from a neutrophil-macrophage progenitor through acquisition of the capacity for autogenous production of PSF and that the autogenous production of PSF might be involved in the mechanisms of leukemogenesis of bone marrow hematopoietic progenitor cells. Heard et al. 23 also showed that there were successive cellular events in the leukemogenic processes of long-term murine bone marrow cultures induced by Friend leukemia virus (F-MuLV), namely, (1) freezing of the normal myelomonocytic differentiation process; (2) change from growth factor (CSF)-dependent to autonomous growth; and (3) acquisition of in vivo leukemogenicity. This in vitro transformation reproduced the course of in vivo leukemogenesis and the experimental system provided a unique example for in vitro investigation of the preleukemic stages of long-term leukemogenesis. C. Growth Factor-Dependent Leukemia Cell Lines Although the mechanisms of successive cellular ~changes in responses to growth factors during leukemogenesis of normal hematopoietic progenitor cells are unclear, some leukemia cell lines have been shown to grow in the presence of autogenous or exogenous growth factors (Table 1). Gootenberg et al. 9 first demonstrated that three cell lines of mature T-cell origin (HUT-102, HUT-78, and CTCL-2) derived from patients with cutaneous T-cell lymphoma-leukemia (CTCL) were constitutive producers of Tcell growth factor (L-TCGF). The L-TCGF from these CTCL lines had the same biological effect as TCGF (IL-2) obtained from normal leukocytes (N-TCGF) of increas-

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Table I G R O W T H F A C T O R - D E P E N D E N T LEUKEMIA CELL LINES Cell line

Originof cell l i n e

HUT-102 HUT-78 CTCL-2 ' ATL-1K ATL-4K ATL-6A ATL-7S ATL-8K ATL-9Y ATL-10Y UK

Humancutaneous T-cell lymphoma Humanadult Tcell leukemia

Eld 35

CDIFVA L 17R

A65T

Growthfactor TCGF" TCGF TCGF TCGF TCGF TCGF TCGF

TCGF TCGF TCGF

Human T-cell lymphoma C3H/HeJmouse bone marrow in 10ng-term culture CD-I mouse bone marrow in loagter~h~ealture AKR mouse thymic lymphoma deriw:d symbiotic leukemia cell line AKR mouse thyrnic lymphoma derived symbiotic leukemia cell line

Ref. 9 9 9 24 24 24 24 24 24 24

TCGF

10

IL3

I9

IL-3 Leukemia growthpromoting factors

Tumor promoters"

26

IL2. b CM of thymir reticuloepitheliaI-likecell line (B6TE). Plant diterpene esters, indole alkaloids, and polyacetates.

"

ing the rate of proliferation of TCGF-independent and TCGF-depeadent CTCL cell lines. On the other hand, the CTCL cell lines produced TCGF and adsorbed TCGF, and showed increased proliferation in response to TCGF. Therefore, this endogenously produced growth factor was suggested to play a role in maintaitling l~roliferation of these leukemic cells in culture as established cell lines independent of exogenous TCGF, although this may not be an essential aspect of leukemogenesis, since "autostimulat i o n " seems to be one of the many changes in phenotypic properties of leukemia cells that gives them a selective advantage for in vitro growth. Salahuddin et al. '~ recently examined soluble lymphokines, including TCGF, in CM from human T-cell lines transformed by human T-cell leukemia-lymphoma virus (HTLV-I). The cell lines used were established 'from patients with T-cell leukemialymphoma and from human umbilical cord and bone marrow leukocytes transformed by HTLV-I in vitro. All but I (UK) of 24 cell lines ,tested grew without exogenous TCGF and constitutively produced I or more of 12 biological activities assayed. These activities were macrophage migration inhibitory factor (MIF), leukocyte migration inhibitory factor (LIF), leukocyte migration-enhancing factor (MEF), macrophage-actirating factor (MAF), differentiation-inducing factor (DIF), colony-stimulating factor (CSF), eosinophil growth and maturation factor (cos. GMA), fibroblast-activating fac-

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tor (FAF), y-interferon, TCGF, IL-3, platelet-derived growth factor (PDGF), and Bcell growth factor (BCGF). These biological activities were detected in unconcentrated tissue culture fluids from most of the HTLV-positive T-cell lines and they were produced constitutively by these cells, unlike by nonactivated T cells from normal donors. However, the role of HTLV in induction of lymphokine synthesis is unclear. Robbet al. 2' recently demonstrated the production of homogeneous TCGF from a human T-leukemia cell line (Jurkat) by immunoaffinity chromatography. Furthermore, the structure of a cDNA for human TCGF has been established by molecular cloning using mRNA from lectin-stimulated Jurkat cells. 2~ These studies indicated that TCGF from Jurkat cells consisted of a single chain polypeptide of 133 amino acids, which constituted residues 21 to 153 of the precursor protein pre-TCGF. Using a highefficiency isolation procedure, Boelen et al. 29 finally isolated TCGF from CM of Jurkat cells. The TCGF had a molecular weight of 15,750 and its amino acid composition was consistent with that deduced from the eDNA sequence coding for this protein. The growth of several murine leukemia cell lines was shown to depend on IL-3. Greenberger et al. ~9 reported that IL-3-dependent mouse hematopoietic progenitor cell lines (Eld35, FLV-A161Vc15, ~,,.'~dCDIFVAcll), derived from long-term bone marrow cultures, produced leukemia in syngeneic adult mice. Unlike other nonleukemogenic hematopoietic progenitor cell lines, these leukemogenic cell lines all released spleen focus-forming virus (SFFV). Thymic stromaI cells, like thyrnic epithelial cells (TEC) and macrophages, have been suggested to be important in routine leukemogenesis. In fact, thymectomy reduced the development of spontaneous lymphatic leukemia in AKR mice and of radiation-induced lymphomas in C57BL/6 mice. a~ On the other hand, transplanted fragments of thymus from high-leukemia AKR strain mice were shown to increase the incidence of leukemia in an Fl hybrid of AKR and C3H mice. ~ Miyazawa et al. 32 recently established a thymic reticuloepithelial-like cell line (B6TE) from normal thymuses of C57BL/6J mice and found that CM from the B6TE cells promoted growth of a murine leukemia cell line (LI 7R) derived from spontaneous thymic leukemia cells of an AKR/ MS mouse. This leukemia growth-promoting factor (LGPF) in the CM of the B6TE cells was heat sensitive (inactivated by heating at 80~ for 2 min), and had a molecular weight of approximately 25,000, judging from its position of elution on Sephadex G100| chromatography. The CM of the B6TE ceils had no activity of IL-l, IL-2, IL-3, or granulocyte-macrophage CSF(GM-CSF). Furthermore, CM of WEHI-3 cells did not promote growth of the L ITR cells. Therefore, LGPF in the CM of B6TE cells is probably different from all the lymphokines described above. LGPF activity was detected in the CM of primary thymic epithelical cells and thymus extract as well as the CM of B6TE cells, suggesting that LGPF plays some regulatory role in the development of normal thymocytes as well as that of thymic lymphoma. Hiai et al. a~'~4 postulated that thymus could provide permissive microenvironments for migrating prothymocyte transformants to progress to autonomously growing Tcell leukemia cells, because they consistently isolated symbiotic complexes of leukemia cells and thymic epithelial reticular cells from primary leukemic thymuses. They found that the in vitro growth and survival of the leukemia cells from such complexes were dependent on close contact with the thymic epithelial reticular cells in a unique form of cell interaction, "pseudoemperipolesis," which these workers defined. 33'3. Furthermore, they sl~owed that tumor promoters, such as 12-O-tetradecanoylphorbol-13-acetare (TPA) and teleocidin, markedly stimulated the in vitro growth of such microenvironment-dependent leukemias without promoting growth of thymic epithelial reticular cells. 26,34These results suggest that the tumor promoters may stimulate the progression of leukemias supposedly occurring in late preleukemic thymuses. To analyze the action of tumor promoters in vitro, Kaneshima et al. 26 recently estab-

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lished a tumor promoter (TPA).dependent cell line, A65T, from a spontaneous AKR/ MS thymic leukemia symbiotically culturetl with thymic epithelial reticular cells. The in vitro growth of the A65T cells was found to depend strictly on the presence of active tumor promoters such as plant diterpene esters (TPA, phorbol-12,I3-dibutyrate, phorbol-12,13-dibenzoate, and mezerein), indole alkaloids (teleocidin and lyngbyatoxin), and polyacetates (aplysiatoxin and debromoaplysiatoxin). The growth-promoting activity of the tumor promoters was reversible and was quantitatively correlated with their tumor-promoting activity in mouse skin. ~6 However, lymphokines such as IL-2 and IL-3 were not responsible for TPA-stimulated growth of A65T cells. 26 Furthermore, TPA did not induce production of any significant amount of these lymphokine activities in the A65T cells. 2~ Thus, this A65T cell line provides a potential model for ap.alyzing growth requirements of developing thymic leukemias. III. E S T A B L I S H E D L E U K E M I A C E L L L I N E S A. Origins and General Properties Pulfertaft 36 first established a human B-lymphoid cell line (Rail) from a biopsy specimen of an African Burkitt tumor. Later, many permanent lymphoid cell lines were established from various leukemia-lyrnphorna patients. In 1972, Minowada et al. 3~ established a T-cell acute lymphoid leukemia (ALL) cell line (MOLT-I to 4) and characterized its phenotype. Since then more than 50 human leukemia-lymphoma cell lines have been established and characterized, as shown in Tables 2 ant r 3. Several myeloid leukemia cell lines have also been established recently (Table 2) and these leukemia cell lines of various cell types have contributed greatly to progress in studies on the biological properties of leukemia cells. These studies have also provided significant information on the characteristics of leukemia, particularly with respect to membrane phenotyping and cytogenetic analysis, ss'a9 Based on these findings on the marker profiles of established leukemia cell lines as well as of numerous fresh leukemia cells, a hypothetical scheme of differentiation of human leukemia cells has been proposed. 3~ It is assumed that lymphoid, myeloid, and erythroid cells differentiate from a single pluripotent stem-cell compartment. In fact, the results of studies on multiple markers of leukemia-lymphoma cell lines suggest that the multiple markers are distributed in each compartment along their respective differentiation lineages, and most leukemia-lyrnphoma cell lines that have been characterized are found to be assigned to a particular compartment of the differentiation lineages.3S.39 On the other hand, overall findings on leukemia-lymphoma marker profiles show a significant heterogeneity of human leukemias reflecting patterns of normal hematopoietic cell differentiation. 3~.39 However, in early studies on surface markers of ALL, ALL was thought to include three distinct diseases, T-, B-, and " null" -cell ALl.,. 48''9 Later, it was shown that the three diseases reflect differences in the point of differentiation of the leukemia target cells. Moreover, some isolated cases of relapse of ALL show changes in the membrane phenotypes from one compartment in the differentiation lineage to another? s,'~ Changes in the membrane phenotypes of leukemic ceils in chronic myeloid leukemia (CML) from granulocytic to lymphoid, mixed myeloid, or even pre-B cells were also reported.Ja.s~ The membrane phenotypes and their marker profiles characterized in myeloid leukemia cell lines also expressed in some normal myeloid cells. 3~.39 Thus, no leukemiaspecific antigen is detected in the myeloid leukemia cell lines, and the heterogeneity of their cellular characteristics may be due to differentiation-linked variation in the leukemia target cells. 3s.39 On the other hand, there is evidence that various myeloid leukemia cell lines and

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CRC Critical Reviews in Oncology/Hematology Table 2 HUMAN

LEUKEMIA-LYMPHOMA C E L L L I N E S ~~

Cell line

Origin of cell line"

CCRF-CEM CCRF-HSB-2 MOLT-l-4 RPMI 8402 HPB-ALL JM MOLT-10 MOLT-11 PEER DND-41 HPB-MLT TALL-1 HD-Mar2 SKW-3 CRFI 1 MJ ATL- 1K ATL-3I ATL-5S MT-I

T-cell leukemialymphoma

BALL- 1 BALM 1-2 NALM6-15 U-698-M BALM3-5 EB-3 RAJI HRIK OGUN B35M AL-1 SL-I NK-9 DAUDI B46M RAMOS BJAB DG-75 Chevallicr DND-39 RPMI8226 U-226 ARH-77

B-cell leukemialymphoma

ALL ALL ALL LS LB BL BL BL BL BL BL BL BL BL BL BL BL BL BL BL MM MM MM

REH KM-3 NALL-I NALM-16 NALM-17,18 KOPNI-8 HPB-Null

Non-T, non-B-ceil leukemia

ALL ALL ALL ALL ALL ALL

U-937

ALL ALL ALL ALL ALL ALL ALL ALL ALL ALL ALL ALL HD(?) CLL ATL ATL ATL ATL ATL

ATL

ALL HL

V o l u m e 3, I s s u e 3 Table 2 (continued) HUMAN

LEUKEMIA-LYMPHOMA C E L L L I N E S z~

Cell line

Origin of cell line' _ - - -_. . . . -

K-562 NALM.I KCL.22 ML-I-3 KG-I HL-60 PL21 THPI RC-2A HL92 GDM-I HEL "

_

Myeloid leukemia

_, ,_,

_

CML

CML CML AML AML APL APL AMOL AMMOL AMMOL AMMOL EL

ALL, acute lymphoblastic leukemia; HD, Hodgkin's disease; C L L , T.cell lymphocytic leukemia;

ATL, adult T-cell leukemia; L$, lymphosarcoma; LB, B-cell lymphoma; BL, Burkitt's lymphoma; MM, multiple myeloma; HL, histiocytic lymphoma; CML, chronic myelocytic leukemia; AML, acute myeloblastic leukemia; APL, acute promyelocytic leukemia; AMOL, acute monocytic leukemia; AMMOL, acute myelomonocytic leukemia; EL, erythroleukemia.

Table 3 MAIN

CHARACTERISTICS, OF LEUKEMIA LINES38.3*

CELL

Cell type of leukemia _ Cell marker

T

E receptor" EAC ~ T-cell antigen B-call antigen Stimulating activity in mixed leukocyte culture

+ (--) +, -+ ---

Common ALLassociated antigen

Epstein-Burr virus infection Terminal deoxynucleotidyl transferase activity "

B

Non-T, non.B

Myr.:loid

+, + +

-_. --+

-+, --+

- (+)

-, +

+

-

-

+ (-)

-

-

High

Low

High

Low

,

Sheep erythrocyte rosettes. Rosettes formed by bovine erythrocyte-lgM antibody-complement complex.

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some lymphoid leukemia cell lines can be induced to differentiate in vitro into mature cells by various agents. These findings suggest that some leukemia cells develop as the result of impairment of a certain stage of differentiation in the normal hematopoietic process. Details of induction of differentiatior~ of leukemia cells and the implications of leukemia cell differentiation will be described later. B. Control of Cellular Growth and Differentiation by Physiological Regulators I. Control of Autonomous Growth Numerous studies on the characteristics and regulation of growth and differentiation of leukemia cells have suggested that leukemia cells may develop by alteration of control of growth and differentiation of hematopoietic progenitor cells. For studies on this altered control mechanism in leukemia cells, establist~ed leukemia cell lines have frequently been used, although these cell lines are usually very different from primary cells taken from the patients or animals with leukemia. These studies showed that the production of growth factors by the cells and the effects of these factors on growth of the cells themselves could be involved in the mechanisms of autonomous growth of some leukemia cells, but the exact mechanisms of the autonomous growth of the various established leukemia cell lines still remain to be examined. This type of autonomous growth does not occur with most primary leukemia cells derived from leukemia patients or with many established leukemia cell lines. Even leukemia cell lines need growth factors, and growth factors produced by the cells, whether or not they are released into the culture medium, may support growth of tt~ese cells. As described previously, many T cells infected with human T-cell leukemialymphoma virus could grow independently of exogenously added TCGF. j~ However, very recently, Arya et al. s' reported that several TCGF-independent T-cell leukemia lines did not contain detectable TCGF mRNA and did not produce their own growth factor. The leukemia cell lines examined included HTLV-positive T-cell leukenlia cell lines (HUT-102, MD, MI, and Mj), leukemia cell lines derived from HTLV-infected normal human cord blood and bone marrow cells in vitro (C5/MJ, CI0/MJ, B2/UK, and MT-2), and an uninfected T-cell leukemia line (HUT-78). in this experiment, the Jurkat cell line, which produces abundant TCGF on treatment with phytohemagglutinin, or TPA, was used as a positive control of a TCGF-producer cell line. As expected, TCGF mRNA was clearly detected in the stimulated Jurkat cells and it was also detected in HTLV-infected HUT-102, MO and HUT-78 cells. However, none of the other HTLV-infected cells contained detectable mRNA. The lack of detectable TCGF mRNA in these ceils was not due to poor quality of the RNA preparations or to other artifacts. These results suggest that TCGF production is not always needed for the proliferation of T-cell leukemia lines and that these cell lines do not have an autostimulation mechanism of growth control. Other possible mechanisms, such as changes in or influences on TCGF receptors sufficient for continued T-cell growth without any growth factor, or growth stimulation by a protein unrelated to TCGF, remain to be examined.

2. Growth Factors and Differentiation-lnducing Factors The growth of normal progenitor cells of macrophages and granulocytes (GM-CFU) and some myeloid leukemia cells can be stimulated by CSF. On treatment with CSF, normal progenitor cells show both proliferation and differentiation into macrophages and granulocytes in vitro. Although most myeloid leukemia cells cannot differentiate on treatment with major molecular species of CSF, some myeloid leukemia cell lines have been induced to differentiate into macrophages and granulocytes by another protein inducer, differentiation.inducing factor (D-factor). 52"~6 CSF can be produced and secreted by various normal and tumor ceils both in vitro

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and in vivo, and its production is stimulated by a number of compounds, s~6~ Recent studies on the molecular properties and biological activities of the CSF have shown that this factor has heterogeneous molecular forms and different biological activities. There are at least three subclasses of molecules in mouse CSF: those that stimulate the production of macrophages exclusively (M-CSF); those that stimulate granulocytes and macrophages (GM-CSF); and those that stimulate neutrophils (G-CSF). 5~'-~j.6~ Analyses of these factors from mice showed that they are glycoproteins with heterogeneous molecular weights: 30,000 to 70,000 for M-CSF, 23,000 for GM-CSF, and 25,000 for G_CSF.Sg.6,.ds In humans, two dis)inct types of C S F - - CSF I and CSF II .--- were found to be produced by various tissues and cultured cells. CSF I could stimulate both human and mouse stem cells and it was purified to homogeneity from human urine and CM of pancreatic carcinoma cells (PaCa-2) and estimated to have a molecular weight of 50,000. 6:' Human urinary CSF I was found to be biologically and immunologically similar to CSF I derived from different human sources, such as CM of pancreatic carcinoma, placenta, lung, and serum. 6:'.6s Furthermore, Das et al. '~' reported that human CSF I and murine M-CSF competed equally with '251-murine M-CSF for binding to murine M-CSF receptors on peritoneal macrophages, but that human CSF I scarcely bound antimurine M-CSF. CSF Ii, with a molecular weight of 27,000 to 30,000, was more active on human than mouse bone marrow ceils and stimulated formation of colonies of granulocytes and macrophages. A third class of CSF, which could stimulate the formation of eosinophiI as well as neutrophil and macrophage colonies from human bone marrow cells but which had little stimulatory activity on mouse bone marrow cells, was purified from CM of a human T-lymphoblast cell line (MO). 7~ In the course of these extensive studies on CSF, its effects on growth and differentiation of myeloid leukemia cells were also examined, mainly with established myeloid leukemia cell lines, lchikawa s2 first reported that CM of mouse embryo ceils could ir~duce differentiation of a mouse myeloid leukemia cell line, M I cells, into mature macrophages and granulocytes. The factor inducing differentiation of MI cells (Dfactor) in the CM was found to be a glycoprotein with an apparent molecular weight of 40,000 to 50,000. The characteristics of this D-factor were distinct from those of CSF. s'sg'6''ds'7'-73 On the other hand, D-factors for MI cells were detected in CM of various cells and tissues and were characterized and purified, s3-sg.6','~5'''-~3 We found that a rat Yoshida sarcoma cell line (YSSF-212) cultured in serum-free medium, ~s a mouse mammary carcinoma cell line (FM3A), 7a a mouse fibroblast cell line (L929),72 and mouse spleen cells treated with poly(1).poly(C), lectins, or immunopotentiators could produce both. D-factors and CSF. ss'717:~ The D-factors were apparently heterogeneous in molecular size, ranging from 25,000 to 80,000. ss-sa,'~',ds.7'-'3 The heterogeneities in molecular size of the D-factors from FM3A and L92, cells were apparently mainly due to differences in carbohydrate contents of the D-factor molecule, since their molecular sizes were markedly reduced by treatment of the cells with tunicamycin, a specific inhibitor of asparagine-linked glycosylation. ''.~2 The apparent molecular sizes of the active components in CSF from these cells and from FM3A and L~2~ cells in the presence of tunicamycin show that the D-factor is distinct from CSF. 7j':': We recently examined the relation of D-factors from various sources using antiserum against partially purified D-factor from mouse L,2~ cell CM. 6' The D-factor had a molecular weight of 50,000 to 70,000 and was distinct from M-CSF. Antiserum to this L-cell D-factor almost completely neutralized the D-factor activity of serum of mice injected with endotoxin and CM from L cells, embryo cells, spleen ceils stimulated with Con A, and lung tissue. However, it did not inhibit the D-factor activity in CM of peritoneal macrophages and differentiated MI cells induced by dexamethasone. The antiserum partially inhibited the D-factor activity in CM of spleen macrophages and

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bone marrow cells. On fractionation of the D-factors from spleen macrophages and peritoneal macrophages, spleen macrophages were found to produce D-factors of two different sizes with molecular weight of 40,000 to 50,000 and 20,000 to 25,000, whereas peritoneal macrophages and differentiated M I cells produced only the smaller molecule. '3 Although antiserum to L-cell D-factor completely suppressed the activity of the large molecular D-factor, it did not suppress that of the small one." These results show that there are at least two types of D-factor for M 1 cells. Antiserum to the D-factor of L cells did not cross-react with CSFs from various sources such as M-CSF from L cells, GM-CSF from lung tissue, and CSFs from macrophage cell line Mm-1 and rat Yoshida sarcoma YSSF-212 ceils. *~Sachs s' also recently reported that D-factor (MGI-2) activity for M1 ceils wa~ separable from CSF activity (MGI-1). Other mouse myeloid leukemia cell lines --- R453 and WEHI-3B were also induced to differentiate into macrophages and granulocytes by CM of various cells and tissues, ascitic fluids, sera of mice injected with endotoxin, or sera from patients with acute myeloid leukemia, sq~2,r4'rs Although the D-factors for R453 cells in rat ascitic fluid were proteinous substances, their relation to the D-factors for MI cells and CSF is unknown. 75 D-factors for WEHI-3B have recently been purified and characterized. Nicola et al. ~2 finally purified the D-factor to homogeneity from CM of the lungs of mice injected with endotoxin and identified it as a G-CSF with a molecular weight of 24,000 to 25,000. The other subtypes of CSF -- M-CSF and GM-CSF --- however, differed sharply in their ability to induce differentiation of WEHI-3B cells: M-CSF was almost completely inactive, and GM-CSF had no detectable activity to induce differentiation of the leukemia cells. With the purified G-CS, the dose-response curves for stimulation of colony formation by normal bone marrow ceils were shown to be essentially identical to those for induction of differentiation in WEHI-3B leukemia cell colonies. 6z Furthermore, it was demonstrated previously that continuous culture of WEHI-3B cells in the presence of G-CSF resulted in complete suppressior~ of self replication of the stern cells, TM and that the leukemogenicity of the WEHI-3B cells was suppressed in syngeneic mice by injection of G-CSF. 6~ However, the mechanisms involved in the response to G-CSF of normal bone marrow cells and leukemia cells remain to be examined. The differentiation of some human leukemia cell lines, such as HL-60, U-937, and ML-I, were also recently reported to be induced by protein inducers (D-factors) in CM from human leukocytes and other ceils. ~7.s~The characterization of these D-factors is now in progress, but, Olsson et al. 7~ showed that human leukocytes stimulated with various mitogens could produce both CSF and D-factors for HL-60 cells with apparent molecular weights of 40,000 and 25,000, depending on the type of mitogen used. This high molecular D-factor was distinct from CSF. On the other hand, ~n some D-factor preparations such as that of lymphokines, interferons were found to be responsible for the activity of the D-factors. Ralph et al. 8' showed that IFN-~, in lymphokines could induce differentiation of U-937 cells into mature monocytes and that IFN-r could induce expression of Fc receptors in myelomonocytic leukemia lines RC-2A and KG-1. Hattori et al. s2 reported that IFN-/~ and natural or recombinant IFN-~ induced differentiation of U-937 cells, but did not induce differentiation of HL-60 cells. We previously showed that IFN-ar and IFN.-fl did not themselves induce differentiation of mouse MI cells or HL-60 cells, but markedly enhanced the induction of differentiation of these cells by D-factor or other inducers. 83.s' However, the activities of D-factors for M I cells derived from mouse spleen cells were distinct from those of IFN, MAF, and CSF. 73'ss Onozaki et al. '6 also reported that the D-factor activity for M I cells in guinea pig lymphokines could be separated from macrophage migration inhibitory factor (MIF) and MAF activities. -

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Thus, the results show that most D-factor activities for M I cells, WEHI-3B cells, and HL-60 cells are distinct from the major part of the CSF activities and other lymphokine activities. Although the role of D-factor without CSF activity in normal hematopoiesis is unclear, D-factor is suggested to control a late stage of differentiation of normal hematopoiesis, since leukelnia M I cells could be induced by D-factor to differentiate without cell mitosis, whereas growth and differentiation in early stages of normal progenitor cells of rnacrophages and granulocytes were suggested to be induced by CSF without D-factor activity. ~'88 Furthermore, mature macrophage.~. and granulocytes produced D-factor. Thus, D-factor can be produced by differentiating normal progenitor cells of macrophages and granulocytes and the differentiation of the progenitor cells can be further stimulated by the D-factor produced. It has been suggested that this mechanism of coupling of growth and differentiation of notmaI progenitor cells is lacking in leukemia cells, s4'89.9t 3. I n h i b i t o r y Factors

Growth and differentiation of normal progenitor cells of macrophages and granulocytes can be controlled by various inhibitors as well as various stimulators, as mentioned before. However, aberrations in the regulation by these inhibitors were detected with cells from patients with leukemia and such defects in negative feedback regulation were suggested to be of importance in the development of leukemia. 929s These inhibitors include lactoferrin, transferrin, acidic isoferritins, E-type prostaglandins, interferon, immunoglobulins, neutropenia-associated inhibitory activity, a leukemia-associated inhibitor (LAI), chalones, chalone-like substances, lipoproteins, and suppressor of stem cells. 92'94'9s The productions and actions of Iactoferrin, transferrin, acidic isoferritin, and E-type prostaglandins have been investigated most extensively. Lactoferrin, a metal-binding glycoprotein, is produced in immature granulocytes and stored in the secondary granules of mature neutrophilic granulocytes. 94'9s it binds to specific receptors on monocytes and macrophages and inhibits the production and release of GM-CSF from these cells with Ia-antigenic determinants. Neutrophi/s from patients with leukemia are quantitatively deficient in lactoferrin, and even the lactoferrin present in them is in a relatively inactive form. 94'95 Another metal-binding protein, transferrin, is biochemically similar to lactoferrin, but differs from it in a few amino acids and in antigenic characteristics. 9s Leukemia-associated inhibitory activity (LAI) was found in bone marrow, spleen, and blood cells of patients with acute and chronic myeloid and lymphoid leukemia, but not in bone marrow or blood cells of normal donors. 94.9s This inhibitory activity was recently isolated, and identified as acidic isoferritins. 96 After isolation and characterization of the inhibitory activity, it was noted that it was similar to a subclass of isoferritin - - acidic isoferritin ---- which had previously been isolated from non-T, nonB lymphoid-like cells, or promonocytes, with Fc receptors. ~6 Although this acidic isoferritin inhibited colony formation of CFU-GM for bone marrow cells of normal donors, it had no effect on CFU-GM from patients with acute leukemia not showing remission or some patients with chronic leukemia or acute leukemia in remission, suggesting a proliferative advantage of abnormally responsive leukemia cells. 9~'~' Broxmeyer et al. 95 recently found that lactoferrin, transferrin, and acidic isoferritins could suppress colony formation by U-937 cells; lactoferrin and transferrin inhibited the release of growth factors from U-937 cells that were needed to stimulate colony formation. Lactoferrin and acidic isoferritins also suppressed colony formation by WEHI-3 ceils, lactoferrin inhibiting the release of growth factors for this colony formarion. 95 It is of interest that lactoferrin, transferrin, and acidic isoferritins can suppress the proliferation of leukemia U-937 cells or WEHI-3 cells, since many cells from leukemic patients were found to be unresponsive to these inhibitors. 9~ It was suggested

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that lactoferrin, transferrin, and acidic isoferritins acted on la-like antigen.positive subpopulations of target cells. 95 Therefore, "regulation of the expression of these lalike antigens may be involved in the mechanisms of response of the target cells to these inhibitors. E-type prostaglandins (PGE~, PGE2) are produced by human monocytes and mouse macrophages and selectively inhibit growth and differentiation of human and mouse progenitor cells of monocytes and macrophages. 94 Lactoferrin has been shown to stimulate production or release of E-type prostaglandins and acidic isoferritins, and thus could give leukemia cells a proliferative advantage over the normal progenitors cells of macrophages and granulocytes suppresssed by the latter two inhibitors. 9~ Broxmeyer et al. 97 examined production of acidic isoferritin in various established cell lines of myeloid lineage and found that the following cell lines contained acidic isoferritin-inhibiting activity that was inactivated by goat antihuman heart ferritin antiserum: HL-60, Raw264.10, J774.16, WEH[-3, MI, RFM, and R453. They found that some cell lines, such as U-937, K562, and B-lymphocyte lines (70Z/3.12, K56F, and 38-C13), contained inhibitory activity that was not inactivated by the antiacidic isoferritin antiserum and were distinct from acidic isoferrit[ns, and that the following cell lines did not contain any detectable inhibitory activity: KG-I, 416B (a stem cell line), RC-2A, GM-86 (an erythroieukemia lille), BM.A and LIOA (B-lymphocyte line), ARH.B and ARH.A (plasmacytoma line), NALM-6, and Jurkat. Interferons inhibited growth of tumor cells and human and murine granulocytemacrophage progenitor cells as well as erythroid progenitor cells. 9' We recently found that IFN-t~,/3 preferentially affected the growth and differentiation of the cell lineage of macrophages in mouse bone marrow. 9s IFN markedly inhibited colony formatiort by macrophages, but not granulocytes from bone marrow in agar cultures, whereas the number of macrophages was significantly increased by IFN in liquid culture of bone marrow cells in the presence of GM-CSF. Therefore, IFN appears to have two actions on growth and differentiation of mouse bone marrow cells: one is inhibition of the growth of early progenitor cells of macrophages, and the other is stimulation of the later stages of growth and differentiation of macrophages. Perussia et al. 99 recently reported that IFN-y, but not IFN-a or IFN-/3, could induce monocytic differentiation in immature myeloid cells from normal human bone marrow or the peripheral blood of patients with chronic myelogenous leukemia. As described previously, a human histiocytic monoblast-like lymphoma cell line, U-937 cells, was shown to be induced to differentiate into macrophages by INF-a, INF-/J, and IFN-y. sl IV. I N D U C T I O N O F D I F F E R E N T I A T I O N OF E S T A B L I S H E D L E U K E M I A C E L L LINES IN V I T R O A. Differentiation-Inducible Leukemia Cell lines and inducers of Cell Differentiation Various myeloid leukemia cell lines and some lymphoid-leukemia cell lines have recently been shown to be induced to differentiate into mature ceils by a variety of compounds, although some leukemia cell lines did not respond to physiological inducers such as D-factors or interferons, as described previously. In this section, these established leukemia cell lines, the compounds affecting induction of differentiation of the leukemia cells, and the mechanisms of induction of differentiation of the leukemia cells are described.

I. Animal Cells Several mouse myeloid leukemia cell lines (MI, R453, and WEHI-3B), mouse Friend virus-induced erythroleukemia cell lines, rat 7,12-dimethylbenzanthracene (DMBA)induced erythroleukemia cell lines (Red-2, REC-I), and a rat Rauscher leukemia virus-

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induced myeloid leukemia cell line (c.WRT-7) can be induced to differentiate in vitro into macrophage, granulocyte, or erythroid cells by various compounds (Table 4). The induction of differentiation of M 1 cells, which were derived from spontaneous myeloid leukemia in an SL strain mouse, into macrophages and granulocytes by D-factor and that of Friend erythroleukemia cells by dimethyl sulfoxide (DMSO) were reported first by Ichikawa sa and Friend et al.; ~~ respectively. Later, various other compounds were also found to induce differentiation of tlaese leukemia cells (Table 4). Other murine myeloid leukemia cell lines have also been established, such as R453 cells from Rauscher leukemia virus-induced leukemia in a C57BL/6 mouse and WEHI3B cells from myelomonocytic leukemia induced with mineral oil in a Balb/c mouse. 7~''2~Although the origins of these leukemias were different, like M I cells, these leukemia cell lines were induced to differentiate in vitro into macrophages and granulocytes by D-factor and other differentiation inducers (Table 4). Rat myelomonocytic c-WRT-7 cells were also induced to differentiate into macrophages and granulocytes by various inducers, although some of these inducers were different from those for other murine leukemia ceils, tl~ On the other hand, Kluge et al. tt9 reported that DMSO could induce DMBA-induced rat erythroleukemia REC-I cells and RED-2 cells to differentiate into erythroid cells. These findings show that leukemia cells retain the capacity for differentiation with an appropriate inducer, irrespective of whether they originated by exposure to virus or to a chemical carcinogen. From extensive studies on inducers of differentiation, mainly using M I cells and Friend erythroleukemia cells, a variety of compounds were found to have inducer activity (Table 4). The chemical characteristics and biological actions of these compounds are so varied that, at present, it is uncertain what chemical structure is essential for induction of cell differentiation. However, possible mechanisms of the induction of differentiation of the leukemia cells will be considered later. 2. Human Cells a. Myeloid Cells Based on findings on induction of differentiation of the leukemia cells in experimental animals, the effects of various compounds on induction of differentiation of human myeloid leukemia cell lines were recently examined. Various myeloid leukemia cell lines that might be blocked at different stages of maturation were induced by a wide variety of compounds to differentiate into macrophage- or granulocyte-like cells or erythroid cells (Table 5). Although the extents of the differentiation of each cell line by different inducers varied, in general the morphological, antigenic, histochemicai, and functional phenotypes of the differentiated leukemia cells were confirmed to be similar to those of mature macrophages, granulocytes, or erythroid cells. '~176176 As described previously, some leukemia cell lines, such as HL-60, and M-I can be induced to differentiate into macrophage-like cells by D-factors. l~176 Furthermore, these cell lines were found to be induced to differentiate into macrophage- and granulocyte-like cells by various other compounds.

i. HL-60 Ceils Inducers of differentiation of myeloid leukemia cell lines were investigated most extensively using HL-60 cells and K562 cells. Collins et al. TM surveyed the effects of the main inducers of differentiation of Friend erythroleukemia ceils on induction of differentiation of HL-60 cells. They found that polar compounds, such as DMSO and laexamethylene bisacetamide, hypoxanthine, and actinomycin D, were potent inducers of differentiation of HL-60 cells, although heroin, ouabain, prostaglandin Et, and dexamemethasone caused no significant induction of differentiation of the cell. Other Cancer chemotherapuetic drugs, such as adriamycin, daunomycin, cytosine arabinoside

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Table 4 DIFFERENTIATION-INDUCIBLE MYELOID LEUKEMIA CELL LINES AND MAIN INDUCERS OF THEIR DIFFERENTIATION: EXPERIMENTAL ANIMALS

Animal Mouse

Type of leukemia/ ceil line

Differentiation inducers

Differentiated cells

Myeloid leukemia, MI

Proteins D-factor, arginase, histone H1

M, G

Lipids Lipopolysaccharide, lipid A, alkyl lysophospholipids, alkylethylene-glycophospholipids Glucocorticoid hormones Dexamethasone Prednisolone Hydrocortisone Vitamin I a,25-Dihydroxyvitamin D3 Polyribonucleotides Poly(l),poly(ADP-ribose) lmmunopotentiaters

M, G

Ref. 52--58, 64--65, 71--73, 88,100 53, 54, 57, 58, 100-- 102

M, 13

53, 54, 56, 58, 100

M, G

58

M, G

58

M, G

58

M, G

58, 103, 104

M, G

74, 75

Mycobacteriem boris BCG, cell wall skeletons (CWS) from Nocardia rubra and Mycobacterium boris

Myeloid leukemia, R453

Myelomonocytic leukemia, WEHI3B

Friend virus-induced erythroleukemia, various cell lines

Others Chloroquin, tunicamyein, latosilan, citrinin Protein D-factor Olucocorticoid hormone Dexamethasone Protein D-factor Vitamins 13-cis-retinoic acid 1a,25-Dihydroxyvitamin Dj Polar compounds Dimethyl sulfoxide, l-methyl-2-piperidone, N,N.dimethyl~tcetamide, Nmethylpyrrolidinone, N,N-dimethylformamide, /~methylformamide, acetamide, triethylene glycol, hexamethylene bisacetamide, tetramethylurea, bisacetyldiaminopentane, cyclohexy!acetamide, N-isopropyl-2-pyridone, N,N'.dimethylcyclic ureas Antibiotics Bleomycin, N.dimethylrifampicin, actinomycin D. actinomycin C, amirmnucleoside of puromycin Purine and pyrimidine analogs, hypoxanthine, l-methyl-hypoxanthinr 2,6-dia-

M, G

75

M, G

59--63

M, G

63

E

105--110

E

106, 111

E

106

E

106, 112, 113

minopurinc, 6-mercaptopurine, 6thioguanine Fatty acids, aldehydes and kctones Na-butyrate, butyraldehyde, pentane dione, butanone, butyrylcholine

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Table 4 (continued) D I F F E R E N T I A T I O N - I N D U C I B L E MYELOID LEUKEMIA CELL LINES AND MAIN INDUCERS OF THEIR D I F F E R E N T I A T I O N : E X P E R I M E N T A L ANIMALS

Animal

Rat

Type of leukemia/ cell line

Myelomonocytic leukemia, cWRT-7

Erythroleukemia, RED-2, REC-!

Differentiation inducers

Differentiated cells

Ref.

Pro[eases a-Chymotrypsin, protease V8 (Staphylococcus aureus), pronase, kallikrein, papain, proteinase K ( Tritfacllium album), bromelein, nagarse (Bacillus subtilis), trypsin Tranqui|izers Diazepan, temazepan Others Prostaglandin E,, ouabain, selenium oxide, selenious acid Lipid Lipopolysaccharide

E

114

E

] ]5

E

106, 116, t 17

M, G

I 18

Tumor promoter 12- O-tetradecanoylphorbol-13-acetate Vitamin Retinoic acid Dirnethylsutfoxide

M, G

118

M, G

118

E

119

(Ara C), vincristine, mitomycin C, and hydroxyurea, were rather weak inducers."' The responses of HL-60 cells to these compounds suggest that human HL-60 cells have cellular target sites in common with Friend erythroleukemia cells for the differentiation-inducing actions of the compounds. However, HL-60 cells markedly differ from Friend erythroleukemia cells in their responses to glucocorticoids and tumor promoters such as phorbol esters, teleocidin, and lyngbyatoxin. ~8.'32''36-'39"1~s The glucocorticoids and the tumor promoters inhibited induction by various inducers of differentiation of the Friend erythroleukemia ceils, but did not suppress differentiation of the HL-60 cells. Glucocorticoids, particularly dexamethasone, were potent inducers of differentiation of mouse M I cells and R453 cells, but they did not affect growth and differentiation of HL-60 cells except to cause some increase in the.number of N-formylated chemotactic peptide receptors on differentiating HL-60 cells induced by DMSO. 15' Various tumor promoters (phorbol esters, teleocidin and lyngbyatoxin) induced HL-60 cells to differentiate morphologically and functionally into macrophage-like cells. ~s''~2''~6"~9 The tumor-promoting phorbol esters had different effects on the differentiation of mouse MI cells depending on the source of serum in the culture medium. ~8'm's' With calf or horse serum, T P A had no effect alone and inhibited the differentiation of MI cells induced by some inducers. In contrast, with fetal calf serum, TPA enhanced the differentiation of M I cells. We found that calf serum and fetal calf serum contained macromolecular factors that, respectively, inhibited and stimulated differentialion. ss'152"'" Induction of differentiation of HL-60 cells by T P A in serum-free synthetic medium was inhibited by the addition of calf serum or fetal calf serum. Calf serum was more inhibitory than fetal calf serum."B Some inducers of differentiation of MI cells, such as arginase, ".':" O.alkyllysophospholipids, ".~2' alkyl ethyleneglycophospholipids, t~176 and l a,25-dihydroxy vitamin D3, TM were also potent inducers of differentiation of HL-60 ceils. However, lipopoly-

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Table 5 DIFFERENTIATION-INDUCIBLE HUMAN MYELOID LEUKEMIA CELL LINES AND MAIN INDUCERS OF THEIR DIFFERENTIATION

Cell line HL-60

Origin" APL

PL-21

APL

K562 '

CML-blast crisis

K562 ~ HEL KG-I ML-!

CML-blast crisis EL AML AML

ML-3 THP-I RC-2A.

AML AMOL AMMOL

" '

Differentiation inducers ~

Differentiated cells

Proteins Arginase Protein inducer

M, G

Lipids Alkyl lysophospholipids Alkyl ethyleneglycophospholipids Vitamins Retinoic acid, 1a,25.dihydroxyvitamin De Polar compounds DM$O, hexamethylene bisacetamide, dimcthy[formamidc Purine and pyrimidine analogs Hypoxanthine, 3-deazauridine, methotrexate, pyrazofurin, virazole, 5-azacytidine 'rumor promoters TPA, t eleocidin, lyngbyatoxin

M, G

Others Actinomycin D, N~sopropyl-2-pyridone,Lethionine, cAMP, marcellomycin, aclacinomycin A, musettarnycin, pyrromycin Cytosine arabinoside, aphidicolin Tunicamycin DMSO Fatty acids Butyric acid, propionic acid Vitamin Vitamin B 12 Antibiotics and anticancer agents Actinomycin D, mitomycin C, bleomycin, cytosine arabinoside, 5-fluorouracil, 6-thioguanine Others . Heroin, d-aminolevulinic acid, cadaverine, 1,6hexandiamine, dithiothreitol, ouavain Arginase, actinomycin D, TPA Heroin TPA, teleocidin TPA, DMSO, cytosine arabinoside, protein inducer TPA, teleocidin, la,25.dihydroxyvitamin D, TPA TPA

Abbreviations as for Table 2. DMSO, dimethyl sulfoxide; TPA, 12-O-tetradecanoyiphorbol-13-acetate. Ceils cultured in normal medium with serum. Cells cultured in serum-free medium for 4 months.

Ref. 10, 58, 61, 65, 66, 77-80, 84, 121-126 58, 10I, 102, I27

G

58, 128-132 132--134

G

132~135

M

E

58, 132, 136-I39 58, 132~ 134, 140-142 t43 144 41, 42, 145, 146 146

E

146

E

146

E

146, 147

M

58, I48

E M M, O

46 66, 149 66, 80, 150 66, 150 43 44

G, M

G

M G, M G

M M M

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saccharide (LPS) and glucocorticoids, which were potent inducers for M1 cells, had no effect on HL-60 cells. S~ On the other hand, retinoids which were potent inducers for HL-60 cells, did not induce differentiation of MI cel~s and tended to inhibit their differentiation induced by some inducers. ~s'l~S.'~6 These results suggest that in various human and routine leukemia cell lines there are several different cellular sites for the inducing actions of inducers. ii. K562 Ceils K562 ceils were found to be induced by heroin '4' or butyrate ~*s to differentiate into erythroid cells synthesizing hemoglobin. Later, Rowley et al. ~46 examined the effects of various compounds on induction of differentiation of K562 cells. They found that a variety of compounds, including many inducers of differentiation of Friend erythroleukemia cells, induced erythroid differentiation of K562 cells and that most of the compounds inducing differentiation in medium containing fetal calf serum had little activity in medium containing newborn calf serum (Table 5). Although erythroid differentiation of K562 cells could be induced in usual culture conditions, the potential or direction of differentiation was modified by change in the culture conditions, sg.t4s.'s7 When K562 cells were cultured iti-~edium deficient in essential nutrients for proliferation, some phenot:cpes showing monocytic, granulocytic, or erythroid differentiation were detected, is7 We found that K562 cells cultured in serumfree medium for a long period (4 months) could be induced to differentiate into rnacrophage-like cells by TPA, arginase, or actinomycin D, whereas when cultured in medium with serum they could not be induced to differentiate by TPA. sg''*s iii. PL-21 Cellsand HEL Ceils Kubonishi et al. 'a.42 recently established two new human rnyeloid leukemia cell lines, PL-21 and KCL-22, from patients with acute promyelocytic leukemia and chronic nayelocytic leukemia, respectively. The pL-21 cells were induced by DMSO to differentiate into mature granulocytic cells in vitro, whereas the KCL-22 cells were not affected by DMSO, but differentiated into granulocytic.cells in vivo in newborn hamsters treated with antithymocyte serum. Martin and Papayannopoulou 46 established a human erythroleukemia cell line, HEL, from the peripheral blood of a patient with Hodgkin's disease who later d.r erythroleukemia. This cell line responded to heroin, showing erythroid differentiationa iv. KO-I, ML-I, ML-3, THP-I, RC-2A, and U-937 Cells Other human acute myelogenous leukemia cell lines, such as KG-I, 66't49 ML-I, 66'ts~ ML-3, ~6.as~THP-I, '3 RC-2A, ~ and,U-937, 66.s~,ts~~63 were found to be induced to differentiate into macrophage-like cells by tumor-promoting phorbol esters or other inducers. Koeffler ~ recently found that KG-I cells and ML-3 cells also differentiated into macrophage-like ceils in response to teleocidins but that other myeloid leukemia cell lines (KG-Ia, U298 ~md K562), which were unresponsive to phorbol diesters, also did not respond to teleocidins. This difference in the response of the latter myeloid leukemia cell lines to these tumor promoters might be due to block at a less differentiated,nayeloid blast stage of maturation. 6~. Retinoids, which are ~otent inducers of differentiation of HL-60 cells, also induced U-937 cells, but not KG-I, ML-3, or K562 cells, to differentiate into macrophage-like cells. 6".j'~ The KG-I cells were extremely sensitive to growth inhibition by the retinoids, showing 50~ inhibition of clonal growth with 2.4 • 10-~ M all trans-retinoic acid. 6~ Proliferation of the KG-I cells was inhibited by the 13-cis form of retinoic acid, but the growth of K562 cells was not affected by the retinoids. 6~The mechanisms by which retinoids induce differentiation and inhibition of growth of leukemia cells are unclear,

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but some specific biological actions, such as alteration of the cell membrane, rather than a nonspecific toxic effect can be considered. 66 The effect of l a,25-dihydroxyvitamin D3, a potent inducer of differentiation of human HL.60 and mouse M I cells, on induction of differentiation of other human myeloid leukemia cell lines was recently examined. The vitamin D metabolite inhibited the growths of HL-60, KG-I, and ML-3 cells at 10-' M and induced the differentiation of HL-60 cells into macrophage-like cells even at i0 "~~ M. 66 Likewise, l0 -7 M l~,25-dihydroxyvitamin D~ induced the differentiation of ML-3 cells into macrophage-like cells. However, it did not induce differentiation of KG-l cells, s~ KG-I cells have been found to contain nearly the same number of receptors for la,25-dihydroxyvitamin D~ as HL60 cells. ~6Therefore, expression of the receptors may not be involved in the mechanism of induction of differentiation of KG-I cells. Recently, U-937 cells were also induced to differentiate into monocyte-like cells by treatment with l a,25-dihydroxyvitamin D~. ~6' Furthermore, it was shown that retinoic acid and l a,25-dihydroxyvitamin D3 had synergistic effect in inducing differentiation of U-937 cells. '64 ML-I cells were induced to differentiate into macrophage-like cells not only by tumor-promoting phorbol esters and teleocidins, but also by Ara C and into granulocytic cells by DMSO. 66,~5~Recently, Hattori et aI. j6~ repoted that lipomodulin, a phospholipose inhibitory protein, and dexamethasone could induce differentiation of U-937 cells into macrophage-like cells. Furthermore, they found that the differentiation by dexamethasone was blocked by monoclonal antilipomodulin antibody, suggesting that the induction of lipomodulin synthesis might be the primary process in dexamethasoneinduced differentiation of U-937 cells. ~62

b. Lymphoid Ceils i. MOLT-3 Cells Although there is relatively little information available on induction of differentiation of lymphoid leukemia cells, compared with that on myeloid leukemia cells, several lymphoid leukemia cell lines, such as MOLT-3, Jurkat, CCRF-CEM, HPB-ALL, and RPMI 8402, have recently been shown to be induced by phorbol esters and other factors to differentiate into cells with more differentiated phonotypes. Nagasawa and coworkers '6s reported that TPA could induce differentiation of MOLT-3 cells and Jurkat cells. After treatment of MOLT-3 cells with TPA, the cells acquired E-rossette-forming ability and lost terminal deoxyribonucleotidyl transferase (TdT) activity. Furthermore, growth of the diffetentiated MOLT-3 cells was arrested without loss in viability. The induction of differentiation of the cells by TPA was not affected by an inhibitor of DNA synthesis (Ara C) or antitumor-promoting compounds (dexamethasone, antipain, retinoic acid, and N-a-tosyl-L-phenylalanyl-chloromethane). Of three other leukemic T-cell lines examined, Jurkat cells responded to TPA and differentiated, but CCRF-CEM and CCRF-HSB-2 cells did not. t6s The inductions of differentiation of MOLT-3 cells and Jurkat cells by TPA were examined further with monoclonal antibodies {OKT3, OKT4, OKT6, and OKT8), which are known to react with human T-cell differentiation antigens. '66 On treatment with TPA, OKT3 § (mature T-cell marker) cells increased but the proportions of OKT4", OKT6 § and OKT8" (relatively immature T-cell markers) cells decreased. These changes were more prominent in MOLT-3 cells than in Jurkat cells. ~* Cassel et al. '67 also examined the effect of another tumor promoter -- phorbol dibutyrate (PDB} -on changes in surface antigen profiles of Jurkat cells with mouse antihuman T-cell monoclonal antibodies. They found that PDB induced rapid and reversible loss of the expression of T4 antigen and a slower increase in Tl ! antigen in the cells, showing that they differentiated to a more mature stage. Recently, Ho et al. '6s examined the effects of thymosin and TPA on enzymes of

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purine metabolism and the cell surface characteristics of MOLT-3 cells. They found that thymosin fraction 5 could induce several changes in the enzymes and the surface phenotypes of MOLT-3 ceils consistent with differentiation in human malignant lymphoblasts of T lineage. The most prominent change was a marked increase in the activity of 5-ectonucleotidase, indicating T-cell maturation, a~ In contrast, decreases in adenosine deaminase activity, proliferating activity, ~nd the percentage of cells that were positive for NAI/34 (monoclonal antibody for pri~nitive T-cell antigen) were observed, j's On the other hand, TPA enhanced the activity of purine nucleoside phosphorylase and the percentage of OKTll (monoclonal anti0ody for an antigen corresponding to sheep erythrocyte receptor)-positive cells, and suppressed cells with TdT activity, but did not significantly affect 5-ectonucleotidase or adenosine deaminase activity, t~s These results show that thymosin and TPA stimulate biochemical or antigenic changes in MOLT-3 ceils that are at least partly consistent with normal differentiation of T cells, although thymosin and TPA cause different phenotypic changes in MOLT-3 cells. it. CCRF-
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ism are generally assurned to be homogeneous, but with a few exceptions cells explanted in vitro tend to lose their original phenotypes spontaneously. 'n The exact mechanisms involved in these changes are unclear, but several in vitro factors affecting genetic and epigenetic properties of the cells may be responsible for these c h a n g e s . " During long-term culture of mouse myeloid leukemia MI cells or WEHI-3B cells, which are sensitive to differentiation inducers, some populations of leukemia cells spontaneously became resistant to differentiation inducers, s6sS.'7' We isolated several' resistant MI cell clones that were resistant to either dexamethasone or the protein inducer D-factor. s~'ss.~Ts'~" The dexamethasone.resistant clones had much fewer nuclear receptor binding sites for dexamethasone than the sensitive MI cell clones. ''7 On the other hand, all the dexamethasone-resistant clones showed less response than the sensitive cells to D-factor, but some clones that were resistant to D-factor were induced to differentiate by dexamethasone. ''7 Then results suggest that the steroid and the protein inducer have different cellular targets. Sachs s3 also characterized various resistant clones from M I ceils and showed that there could be blocks at different stages of differentiation by a variety of inducers and that there were distinct controls for the induction of each pheaotype of differentiation. Ichikawa et al. 87 and Nagata et al. 17~.~79 reported that actin from D-factor-treated, differentiating M I cells could polymerize, but that it could not polymerize with actin from M 1 clone cells resistant to the D-factor. We found that M I cell clones resistant to D-factor or dexamethasone, but not Dfactor-sensitive clones, produced an inhibitory activity (I activity) for induction of differentiation of MI cells. ~s~The I activity was due to heat-labile, macromolecular (nondialyzable) proteins. `s~ Production of I activity in resistant M1 cells was closely associated with resistance of the cells to differentiation inducers, since inhibition of synthesis of this I activity by a low concentration of actinomycin D concomitantly restored the sensitivity of the resistant cells to the inducers. ~s~ We found that other inhibitors of RNA or protein synthesis (chromomycin A3, nogalamycin, cordycepin, puromycin, and cycloheximide) cot, ld sensitize the resistant clones of MI cells to D-factor. '7~ Furthermore, we found that some anticancer agents (adriamycin, duanomycin, mitomycin C, hydroxyurea, 5-fluorouracil, and bleomycin), interferon, and DMSO also sensitized resistant MI cells to D-factor, although these substances alone could not induce differentiation of the cells. TM These findings suggest that some of the anticancer agents in the presence of differentiation inducer control tumor growth by their ability to induce differentiation of the cells as well as by their cytotoxic actions~ Recently, we examined the effect of I activity from resistant M 1 cells on growth and differentiation of normal mouse precursor cells of macrophages and granulocytes in i>one marrow. 's2 The I activity markedly inhibited colony formation of the precursor cells induced by' CSF in soft agar medium, and this inhibition by I activity of resistant MI cells was reduced by treatment with a low concentration of actinomycin D. Although it is unknown whether the I activity against normal precursor cells is identical with that against leukemia M I cells, the results suggest that I activity may give the leukemic cells leukemogenic advantages by inhibiting normal hematopoiesis. As described previously, normal hematopoiesis can be negatively regulated by inhibitors from various sources. We examined the relation between one of these inhibitors, acidic isoferritin, which inhibits proliferation of normal granulocyte-macrophage precursor cells and the I activity from resistant M I cells. ~s3 Ant/acidic isoferritin serum did not neutralize the I activity that inhibited differentiation of sensitive MI cells. However, the antiserum neutralized the inhibitory action of the I activity on growth and differentiation of normal precursor cells of granulocytes and macrophages in bone marrow. ''3 Therefore, the inhibitory activity for differentiation of MI cells from resistant M I cells is different from acidic isoferritins.

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b. R453 Cells and WEHI-3B Cells Other murine myeloid leukemia cell lines -- R453 and WEHI-3B -- can be induced by D-factor or glucocorticoid hormone to differentiate into macrophages or granulocytes. ~7-6a'74'76Actinomycin D, at low concentrations, markedly enhanced by the induction of differentiation of R453 cells '5 and a subclone of WEHI-3B cells, WEHI3BM6, '~4 which was resistant to the differentiation inducer. Addition of other inhibitors of synthesis of RNA (chromomycin A3 and nogalamycin) or protein (puromycin) to R453 cells also enhanced the induction of differentiation of the cells. TM 2. Human Cells Recently, the inducibility of differentiation of some populations of human myeloid leukemia cell lines, such as HL-60, K562, and KG-I, has been reported to decrease during long-term culture either spontaneously or in the presence of low concentrations of various inducers of differentiation of leukemia cells. These resistant cell populations were isolated by cloning and their properties were examined. a. HL-60 Cells Bodner et al. ~84 isolated 6-thioguanine (TG)-resistant HL-60 cells (HL-60 TG-20) by culturing HL-60 cells with increasing concentrations of TG of up to 20 ~g/mi. These TG-resistant cells had chromosomal markers and the distribution of their chromosome numbers was similar to that of the parent HL-60 cells. However, compared with the parent cells, the TG-resistant cells had a lower rate of spontaneous terminal differentiation and increased resistance to induction of differentiation by DMSO, dimethylformamide, or hypoxanthine, which were inducers of differentiation in the parent HL-60 cells. The TG resistance of the TG-20 cells was suggested to be due to deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRT). On the ottler hand, two types of TG-resistant sublines of HL-60 ceils were recently isolated by Fitz-Gibbon et a]. '"5 The first type (clone 20TG20) did not differentiate on treatment with hypoxanthine, but responded to DMSO and retinoic acid and matured into granulocytic cells. The five clones of the second type, selected for resistance to DMSO, did not respond to any of the other agents, such as hypoxanthine, retinoic acid, and actinomycin D. These resistant clones had also lost peroxidase activity and granulocyte antigen. Therefore, the factors controlling inducibility of differentiation and these phenotypir characteristics may be related. Gallagher et al.'*' examined phenotypic and genetic changes in TG-resistant sublines of HL-60 cells that were sequentially selected with increasing concentrations of TG of 0.5 to 50 ~g/ml. The resistant sublines showed no significant quantitative changes in key enzymes of purine metabolism other than HGPRT deficiency. Furthermore, the TG-resistant cells showed no change in rate of hypoxanthine membrane transport. However, results suggested that there was a consistent relation between double-minute chromosomes (DMC) in the TG-resistant cells and the differentiative response to TG, although other DMSO-resistant sublines had neither double minutes nor chromosomal homogeneously staining regions. Variant HU-60 cell clones (C12 and C13) resistant to DMSO were isolated from cultures containing 1.25% DMSO. '87 These DMSO-resistant clones had similar morphological and cytochemical characteristics to those of the parent HL-60 cells, but a different karyotype with marked hyperploidy. Both the resistant clones were induced to differentiate by retinoic acid and TPA, although the CI3 cells showed lower responses to these inducers. Seven DMSO-resistant clones of HL-60 ceils were isolated from cultures of HL-60 cells infected with SV40 virus (HL-60 m2 and m4), or treated with alpha particle radiation (HL-60Ast 1, 3, 4, and 25) or from untreated culture of HL-60 cells. 's8 These resistant cells were morphologically and cytochemically similar

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to the original HL-60 cells and could be induced by TPA to differentiate into macrophage-like cells. The resistant clones HL-60 m2, m4 and Ast 25 responded to DMSO at higher concentration (1.5 to 1.75%) and differentiated into granulocytic cells. 'as Recently, several TPA-resistant clones of HL-60 cells were isolated and characterized. Au et al. lap examined DMC and other chromosomal changes in sublines of HL60 cells that showed various degrees of resistance to induction of differentiation by TPA. The parent HL-60 cells sensitive to TPA, contained DMC and the sublines with different degrees of resistance to TPA showed a corresponding sequential reduction of the DMC. However, this loss of the DMC was not associated with the appearance of homogeneously staining chromosomal regions. Other chromosomal changes were also detected in the resistant sublines, t89 Murao et al. '.9~examined the effect of le,25-dihydroxyvitamin D3 on induction of differentiation of two variant cell lines of HL-60 cells - - R-80 and B-11 -- which were resistant to induction of differentiation by TPA and DMSO, respectively. R-80 cells also showed resistance to induction of cell differentiation by la,25-dihydroxyvitamin Da, but the resistance to the two compounds may not be due to their similar binding sites in the cells, since la,25-dihydroxyvitamin D3 did not compete with TPA for binding sites. B-II cells were resistant not only to DMSO, but also to the differentiation inducers l a,25~ D3 and TPA. A tetraploid variant of HL-60 cells (HL-60TR) was isolated recently from ceils cultured with TPA for 1 week. '9~ These HL-60TR cells were resistant to induction of differentiation by TPA. In addition, the resistant cells released a factor that inhibited induction of differentiate.on of the parent HL-60 cells by DMSO or L-ethionine. This inhibitory factor also suppressed colony formation by CSF of normal bone marrow cells. Preliminary studies on the inhibitory factor in CM of the resistant HL-60TR cells showed that it was a heat-labile (inactivated by heating at 60~ for 1 hr) and nondialyzable macromolecule and that it was precipitated at 90% with saturation of ammonium sulfate. '~' The general characteristics of this inhibitory factor seem to be similar to those of the inhibitory activity (I activity) from the differentiation-resistant clones of mouse MI cells described previously, 18~ although its identification with the latter requires study.

b. K562 Cells and KG-I Ceils The variations in inducibility of differentiation of K562 cells in different culture conditions and those in sublines of KG-I cells were recently examined. Dimery et al. ,92 studied K562 cells that had been maintained in three different laboratories (A, B, and C) outside their institution and designated them according to their source as K562A, K562B, and K562C. The characteristics of these three cell lines with respect to morphology, growth kinetics in liquid suspension culture, cloning efficiency in soft agar culture, binding of anti-KS62 monoclonal antibodies, and most cell surface proteins were in general similar. In contrast, their inducibilities of hemoglobin synthesis by hemin were significantly different, K562A being the most sensitive. '92 Two membrane proteins (93 and 85 kdaltons) and one membrane protein (93 kdaltons) were detected in K562A and K562B, respectively, but neither of these proteins was detected in K562C. tpa None of the cells responded to another inducer of differentiation, sodium butyrate, suggesting that the cells differed from those reported by Andersson et al. ~4s in this respect. Tsuruo et al. ~9~recently isolated a variant clone of K562 cells (K562/VCR) that was resistant to the cytotoxic actions of anticaneer drugs such as vincristine and adriamycin. They found that verapamil, a calcium channel blocker, could sensitize this resistant clone to these drugs by inhibiting active efflux of the drugs. We examined the effects of several inducers of differentiation of the parent K562 ceils on induction of

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differentiation of the resistant K562/VCR cells. '~' Differentiation of K562/VCR cells was not induced by aetinomycin D or adriamycin alone, hut the resistance of these cells to the inducer was overcome by verapamil. In contrast, mitomycin C, butyric acid, and heroin induced differentiation of K562/VCR cells as effectively as that of the parent K562 cells. These results suggest that tt~e target sites on the resistant K562/VCR cells for differentiation inducers such as heroin and butyric acid are different from those for vincristine and adriamycin, and that the resistant cells are sensitive to specific inducers such as hemin and butyric acid. Therefore, in vivo induction of terminal differentiation of leukemic cells that are resistant to cytotoxic anticancer drugs may be an alternative therapeutic approach to control of leukemia. Lehrer et al. tgs recently examined the binding characteristics of phorbol diester in a cloned subline of KG-I cells (KG-I-a) that could not be induced to differentiate by phorbol diesters and was assumed to be morphologically, histochemically, and functionally arrested at an undifferentiated blast stage. Both KG-1 and KG-I-a cells had a single class of specific high affinity receptors for [3H]phorbol-12,13-dibutyrate and they had similar numbers of [3H]phorbol-12,13-dibutyrate binding sites per cell. Furthermore, Lehrer et al. ~gs could not detect any significant decrease in specific binding of the phorbol diester with time (down regulation) iii either KG-I, KG-I-a, or HL-60 cells. These results suggest that down regulation of specific phorbol diester binding is not cruciai for induction of cell differentiation and that the presence of specific high affinity receptors of the phorbol diester on the leukemia cells assures that phorbol diesters can trigger cell differentiation. C. Mechanisms of Induction of Myeloid Leukemia Cell Differentiation 1. Control of Cell Differentiation in Membrane and Nucleus The molecular mechanisms that control leukemia cell differentiation are poorly understood, although they have been studied extensively in several leukemia cell lines such as Friend erythroleukemia cells, MI cells, WEHI-3B cells, and HL-60 cells. Most rcsults suggest that modifications by differentiation inducers of cellular components in either the membrane or nucleus are involved in the mechanisms. We observed marked changes in membrane components, such as phospholipids and glycoprotcins, during induction of differentiation of MI cells into macrophagcs and granulocytes? 7,'.'9~ Furthermore, enzymes of prostaglandin synthesis were induced in the differentiating MI ceils and prostaglandin E2, D,, and F~ were produced in an early stage of differentiation, although mature cells produced mainly prostaglandin E2. s~-sS.'97 The syntttesis of E-type prostaglandins was found to be involved in the mechanisms of differentiation of M I cells since nonsteroidal antiinflammatory agents (salicylate, phenylbutazone, and indometacin) and antioxidants (butylated hydroxyanisole and butylated hydroxytoluene) that inhibited synthesis of these prostaglandins blocked the induction of differentiation of M I cells by various inducers, s~-" Prostaglandins E,, E2, and D~ induced lysozyme activity and stimulated differentiation of M I cells induced by a suboptimal concentration of inducer, whereas prostaglandin F2o inhibited the induction of differentiation by dexamethasone, ss.~9' Prostaglandins F2o and B-type prostaglandins stimulated production of material with differentiation-inhibiting activity that was a heat-labile proteinous substance, but A-, E-, and D-type prostaglandins did not. ''~gs These results suggest that different types of prostaglandins regulate differentiation of M 1 cells. The ratio of phosphatidylethanolamine to phosphatidylcholine increased markedly to nearly that of normal macrophages during differentiation of MI cells induced by several inducers (dexamethasonr LPS, arid D-factor). "'1~6 During differentiation, the incorporation of methyl groups into phosphatidylethanolamine in MI cells decreased, while the incorporation of choline into phosphatidylcholine increased slightly, suggest-

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ing that decrease of cellular phospholipid methylation is partly due to decrease of methyltransferase activity. Culture of M1 cells with the choline analogs N-monomethyIethanolmaine and .N,N'.dimethylethanolmaine, resulted in accumulation of phosphatidyl- N-monomethylethanolamine and phosphatidyl.-N-dimethylethanolamine, respectively, in the cell membrane. '9+.~99This change on treatment with choline analogs was associated with morphological and functional differentiation of M1 cells into macrophages and granulocytes. On the other hand, we found previously that O-alkylphospholipids, which might cause disturbance of phospholipid metabolism, induced differentiation of MI cells, s+.~m.~~ These findings suggest that changes in phospholipid metabolism play a role in the mechanisms of differentiation of M1 cells. Differentiation-associated functional changes, such as phagocytosis and motility of M I cells, were reversibly inhibited by cytochalasin B. ~' This suggests that changes in cytochalasin B-sensitive proteins containing actin, such as those in microfilaments, may be involved in the mechanisms of cell differentiation. Later, increase in the actin content and polymerization of G-actin in the differentiating MI cells reported by Hoffman-Liebermann and Sachs 2~176 and Nagata et al. J~s Nagata and Ichikawa T M showed that a thymidine analog, 5-bromodeoxyuridine (BrdU), could inhibit induction of differentiation of MI cells, although some phenotypes of a certain clone of M I cells were reported to be induced by BrdU. This inhibitory effect of BrdU on the induction of cell differentiation was prevented by the addition of excess thymidine, and BrdU had no effect on a BrdU-resistant cell line. On the other hand, actinomycin D at 30 to 50 ~g/m! or puromycin at a concentra.tion of more than 2,5 x 10-~ M markedly inhibited the induction of differentiation of MI cells, 2~

2. Positive Feedback Control by Differentiation-Stimulating Factors Produced in Differentiating Cells Differentiating MI cells produce some factors that promote induction of differentiation of the cells. We found that MI cells could be induced by glucocorticoids to produce a glycoprotein with a molecular weight of 20,000 to 40,000 that stimulated induction of M I cell differentiation. 57.5~,2~ Production of this glycoprotein could not, however, be induced in dexamethasone+resistant M I cells that could not differentiate even with a high concentration of dexamethasone. Thus, production of the glycoprotein was associated with differentiation of M I cells, and the glycoprotein seemed to contribute as a mediator to positive feedback regulation of differentiation of M 1 cells. Sachs ~3"5+also reported that some clones of MI cells could produce a differentiationstimulating factor for MI cells when treated with various compounds [LPS, phorbol esters, and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)]. These workers examined the regulation of induction of two activities, CSF (MGI-I) and D-factor (MGI-2), during differentiation of MI cells induced by NMNG or LPS. u They found that CSF was induced before D-factor, showing that regulation of its induction was different from that of D-factor in MI cells. Production of CSF in differentiating MI cells induced by LPS without any significant production of D-factor was also observed by Maeda and Ichikawa. 2~

3. Cell Cycles and Control of Cellular Growth and Differentiation The relation between the cell cycle of MI cells and commitment to cell differentiation was examined with D-factor in CM of hamster embryo cells. T M When MIB24 cells were treated with the D-factor, they traversed the S phase of the cell cycle at least once. Then a fraction of the cells lost the ability to enter the S phase and accumulated in the G 1 phase. DNA synthesis in the differentiated cells decreased after treatment with the D-factor for 12 to ! 8 hr and the cells differentiated markedly during treatment with Dfactor for 24 hr. Induction of phagocytosis was examined in MIB24 cells that had been

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prelabeled with [~H]thymidine. No significant difference was found between the phagocytic activity in the labeled and unlabeled cells. Therefore, M IB24 cells in any phase of the cell cycle can respond to the D-factor and can be initiated to differentiate. The finding that there is no specific phase of the cell cycle at which induction of M IB24 cells occurs seems consistent with previous observations by lchikawa et al. *' that M I cells could be induced to differentiate under conditions when DNA synthesis was blocked by 5-fluorodeoxyuridine. In human myeloid leukemia cell lines (HL-60 cells and KG-I cells), DNA synthesis was also shown to be independent of development of phenotypes of differentiated macrophages, s' The proportion of differentiating cells, among the total myeioid leukemia cells was found to depend on the concentration of inducer. Moreover, the cell population was shown not to differentiate synchronously, although details of the mechanisms of induction of this asynchronous differentiation in the ceils remain to be examined. We found that the process of differentiation of MIB24 cells was promoted by increasing the concentration of D-factor; the transition of M I B24 cells from the undifferentiated state to the differentiated state occurred in a stochastic manner; and the proportion of well-differentiated cells in the whole ceil population was higher at higher concentration of the D-factor. 2~ The proliferative activity of individual MIB24 cells decreased at a specific stage of differentiation and this decrease was independent of the culture time of the ceils and the concentration of D-factor. ~~ Therefore, the production of differentiated cells is regulated by a balance between proliferation and differentiation of the cells that is dependent on the concentration of the D-factor. High concentrations of D-factor in CM from embryo cells or spleen macrophages were shown to suppress the formation of MI cell colonies in agar medium, s2'ss's' Metcalf ~~ found that the fraction of colony-forming cells in a WEHI-3B cr population gradually decreased and finally disappeared completely during serial recloning in the presence of a protein inducer, postendotoxin mouse serum. These results suggested that, in principle, the mechanisms regulating the kinetics of proliferation and differentiation of this cell population of leukemic cells are similar to those of MIB24 cells. Crissman and Steinkamp 2~ developed a method for simultaneous analysis of DNA and protein in the same cell by flow cytometry (FCM). In this method, DNA and protein in individual cells are stained with propidium iodide and fluorescein isothiocyanate, respectively~This FCM method permitted precise kinetic measurements of changes in DNA and protein content of the cells in all stages of the cell cycle. We recently examined the kinetics of changes in the contents of DNA and protein in M IB24 cells during their differentiation into macrophages by this FCM technique. ~~ When M IB24 cells were treated with various concentrations of D-factor, ceils with a 2C DNA conten~,., G l / 0 cells, increased and protein accumulated in these G I / 0 cells. The increases in the number of G l / 0 cells and in their protein content per cell were proportional to the concentration of D-factor. Serial analyses of changes in the contents of DNA and protein in the differentiating MIB24 cells showed that DNA synthesis was suppressed by differentiation-induced block of the cell cycle at the G I / 0 phase, but that increase in the protein content was not completely suppressed by block of the cell cycle. 2~ Therefore, unbalanced control of the DNA and protein contents of M I B24 cells may be involved in their mechanisms of differentiation.

4. Control of Oncogene Expression Recently, certain DNA sequences homologous to the oncogenes of tumorigenic retroviruses (cellular oncogenes, c-one)were suggested to have a role in regulation of growth and differentiation of both normal and leukemic myeloid cells. Westin et al. 2~176 examined expression at the mRNA level of a cellular oncogene-- myb gene (cellular homolog of the transforming gene of avian myeloblastosis virus [AWV]) - -

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in various human fresh peripheral blood cells, cultured leukemia cell lines, and other solid tumor cell lines, including carcinoma, sarcoma, melanoma, and glioblastoma. Results showed that the myb gene was expressed in the mye|oid (KG-I and HL-60), erythroid (K562), and T-lymphoid leukemia cell lines (CEM, MOLT.4, KM-3), but not in B-lymphoid leukemia (Daudi and Rail), more differentiated T-mymphoid leukemia (HUT-78 and HUT-102), or solid tumor cell lines. In addition, expression of the myb gene was found to be markedly suppressed in differentiated HL-60 cells induced by DM$O or retinoic acid. 2~176 Decrease in the expression of the myb gene was also recently observed in differentiation-induced myeloid leukemia cell lines KG-1 and ML1.66.2~o Furthermore, it was shown that the decreas,~d mybexpression was an early event in the loss of proliferation of ML-I cells that accompanied TPA-induced differentiation of the cells. 2t~ Another oncogene, myc, a cellular homolog of avian myelocytomatosis virus strain MC29 that induces B-cell lymphomas in chickens, is markedly expressed in HL-60 cells and KG-I cells. ~6.'~176 Transcription of this gene is suppressed on induction of differentiation of the HL-60 cells by DMSO, retinoic acid, or l a,25.dihydroxyvitamin D~. 2~ Its expression is also decreased in differentiated KG-I cells. 66 Moreover, Reitsma et al. TM showed that phenotypic changes associated with differentiation by l a,25-dihydroxyvitamin D3 are preceded by marked reduction in its expression. Grosso and Pitot ~'2.2t~ recently examined the effects of inducers of differentiation (DMSO, cycloleucihe, sodium butyrate, theophylline, 3-aminobenzoate, TPA, and mezerein) and inhibitors of cell proliferation (papaverine, hydroxyurea, and dexamethasone) on expression of the myc gene in HL-60 cells. They found that expression of this myc gene was inversely correlated with the state of differentiation of the cells, irrespective of the nature of the inducer or the rate of cell proliferation. Furthermore, a cellular homolog of the viral fes gene, which induces sarcomas in cats, was found to be expressed in both HL-60 cells and KG-I cells, and its expression was shown to be decreased in differentiated cells. 66These results suggest that the mechanisms of induction of differentiation of myeloid leukemia cells involve suppression of oncogene expression. V. C O N T R O L OF M O U S E M Y E L O I D L E U K E M I A CELL P R O L I F E R A T I O N IN VIVO BY I N D U C E R S OF CELL DIFFERENTIATION In vivo inducibility of differentiation of myeloid leukemia M1 cells was first examined using the diffusion chamber technique. Two types of clones of MI cells, clones that were sensitive and resistant to inducers of differentiation, were put into diffusion chambers in syngeneic SL mice and their morphological changes were examined, s'.sb-s',2'' The sensitive cells were induced by some endogenous factors in mice to differentiate into mature macrophages and granulocytes, losing their capacity to proliferate, while the resistant cells remained undifferentiated. ~6ss,2E4These resistant cells were much more leukemogenic in the syngeneic SL mice than the sensitive cells, and the survival times of mice inoculated with them were less than those of mice inoculated with the sensitiv,- "Is.sb"sa'2z' These results suggested that the in vitro and in vivo inducibility of d :iation of the leukemia cells is related to the leukemogenicity of the cells in syr mice. We examined the re between leukemogenicity and in vivo inducibility of differentiation of leuken'under natural conditions without any artificial barriers that prevented cell-to-action of the inoculated leukemia cells in the diffusion chamber with immune at cells of the host. We labeled MI cells in vitro with [~H]thymidine and inj m directly into the peritoneal cavity of syngeneic SL

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mice. ~,2~'~ After several days, the M I cells, identified by autoradiography, had differentiated into macrophages and granulocytes, When LPS, an inducer of cell differentiation, was injected into the mice, differentiation of the isotope-labeled cells was significantly stimulated. These results show that M1 cells, can be induced to differentiate in vivo under conditions in which leukemia can develop. Next, the therapeutic effects of administration of the differentiation inducers on mice inoculated with M1 cells were examined. 5658 The inducers (LPS, dexamethasone, D-factor from CM of Krebs ascites tumor cells, la,25-dihydroxyvitamin D~, and alkyl ethyleneglycophospholipids) significantly enhanced the survival times of mice inoculated with M I cell clones that were sensitive to these differentiation inducers, s4'5osS.~~ However, the survival times of the mice inoculated with MI cell clones that were resistant to differentiation inducers such as LPS and dexamethasone were not affected by these inducers. 5658.2~4,2'~ These effects are consistent with the effects of the inducers on induction of differentiation of sensitive and resistant cells in vivo and in vitro. The resistant MI cell clones could be sensitized by actinomycin D to the differentiation inducers in vitro. 56-'.~76 Therefore, we examined the in vivo effect of actinomycin D on differentiation of the resistant MI ceils. Acfinomycin D at a low dose was found to sensitize the resistant MI cells in diffusion chambers in mice to ettdogenous inducers, resulting in their differentiation into macrophages and granulocytes? ~-ss,~Is Thus, the survivals of mice inoculated with the resistant M I cells were markedly prolonged by treatment of the mice with actinomycin D. Administration of actinomycin D plus LPS or alkyl ethyleneglycophospholipid to the mice enhanced the therapeutic and differentiation-inducing effects of actinomycin D alone, t~ Lotem and Sachs z'6 showed that D-factor from CM of Krebs ascites tumor cells enhanced the antitumor effect of cyclophosphamide on MI celL-inoculated mice, suggesting that the D-factor and.cytotoxic anfitumor drug had synergistic therapeutic effects on myeloid leukemia. Poly(1).poly(C) was found to increase the sensitivity of MI cells to D-factor and stimulate production of D-factor by mouse peritoneal macrophages, sT.~s.6~ It also greatly prolonged the survival times of mice inoculated with either sensitive or resistant clones of MI ceils, 57.'.'s.2'~ and it was much more effective than poly(A)'poly(U) or poty(l) in mice. ~t~ The serum levels of interferon and D-factor activities in mice were markedly increased by injection of poly(1), poly(C), and remained significantly increased for 72 hr after treatment, s~'~',2t9 These activities wei'e found to be responsible for in vivo induction of differentiation of M I cells and prolongation of the survival times of the mice, s7'''2~9 We also found recently that administration of interferon (L-cell derived) alone prolonged the survival times of mice inoculated with a sensitive MI cell clone. ~2~ Vl. C L I N I C A L STUDIES O F E F F E C T S OF D I F F E R E N T I A T I O N I N D U C E R S ON N O N L Y M P H O C Y T I C L E U K E M I A A. Induction of Differentiation of Fresh Leukemia Cells in Primary Culture Based on results on induction of differentiation of established leukemia cell lines, the effects of some inducers of differentiation on fresh human leukemia cells in primary culture were examined. The therapeutic effects of some differentiation inducers, including currently used antitumor drugs, were also recently evaluated. Palu et al. ~J',~2~found that fresh leukemic cells in primary culture from patients with acute myelogenous leukemia (AML) differentiated spontaneously into macrophage- or granuloeyte-like cells during culture concomitantly with cessation of proliferation and leukemogenicity in nude mice. Several inducers of differentiation of established leukemia cell lines were also found to be effective for stimulating differentiation of fresh

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human leukemic cells in primary culture. One of these inducers -- TPA --- induced fresh human leukemic ceils from patients with various types of myeloid leukemia to differentiate into macrophage-like cells. **'~~ Recently, TPA was atso found to induce fresh human leukemic cells from patients with chronic lymphocytic leukemia (CLL) to differentiate into celIs with some of the characteristics of mature B cells, showing change in morphology, reduction in surface immunoglobulin (Ig), appearance of cytoplasmic Ig, secretion of IgM, the mixed lymphocyte reaction, and increased sensitivity to lysis by natural killer cells. 22s'232 Other inducers of differentiation of myeloid leukemia ceil lines, such as retinoic acid, la,25-dihydroxyvitamin D3, DMSO, actinomycin D, alkyl lysophospholipids, butyrate, and CSF, also induced several types of human fresh acute nonlymphocytic leukemia cells to differentiate into granulocyte- or macrophage-like cells, sg'6o'tant32.226,2a~-2as However, the most effective inducer differs with different types of leukemia and different specimens of leukemic cells. The therapeutic values of physiological inducers, such as retinoids (vitamin A and its analogs) and the active metabolite of vitamin D (la,25-dihydroxyvitamin D3), have also been investigated recently. 5s'66''a~ Results suggested that besides triggering differentiation of leukemia cells, retinoids modify the proliferation and differentiation of normal and leukemic hematopoiesis by alterating the membrane components of hematopoietic progenitor cells, ss.66.t3~ Therefore, retinoids may exert their therapeutic effects by these various biological actions, la,25-Dihydroxyvitamin Dj induced only parti'al differentiation of myelogenous blast cells from leukemic patients into macrophage-like cells, and modified the proliferation and differentiation of bone marrow hematopoietic progenitor cells, although it ', mechanisms of action are unknown. 6~ Recently, the synergistic effects of retinoic acid with prostaglandin E2 or protein inducer, D-factor, on in vitro induction of differentiation of fresh human acute promyelocytic leukemia cells were examined. ~3~ Prostaglandin Ez alone had no effect on differentiation of the cells, but a combination of prostaglandin E~ (10 nM)and retinoic acid (100 taM)slightly stimulated differentiation of the cells, ~3~ and a combination of D-factor and retinoic acid had a marked synergistic effect on induction of their differentiation, t~2 We recently examined the effects of various inducers of human myeloid leukemia cell lines on in vitro induction of differentiation of fresh leukemia cells from patients with acute myeloid leukemia in relapse, a~o Leukemic cells from most, but not all, patients responded to TPA, retinoic acid, actinomycin D, aclarubicin, and alkyl lysophospholipid, and differentiated into monocyte-macrophage-like cells or granulocytelike cells, although the most effective inducer varied with the cell specimen. Results on leukemic cells from patients in relapse were usually comparable with those on cells from untreated patients. The responsiveness to TPA of leukemia cells from patients in relapse was similar to that of leukemia cells from untreated patients. TM However, retinoic acid or actinomycin D was ineffective more often with leukemia cells from patients in relapse than with those from patients before initial therapy. TM These results, together with previous findings that the target sites on anticancer drug-resistant human leukemia cells for differentiation inducers are different from those of anticancer drugs, suggests that inducers of differentiation may also be effective for induction of remission of leukemia. B. Effects of Administration of Differentiation Inducers on Leukemic Patients Therapeutic trials were recently made on several inducers of differentiation of established leukemia cell lines. Flynn et al. 237 reported that 13-cis-retinoic acid induced both in vitro and in vivo differentiation of leukemic ceils from a patient with acute promyelocytic leukemia that was refractory to chemotherapy. Gold et al. 23' administered 13-

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cis-retinoic acid to 19 patients with the myelodysplastic syndrome and found that 3 of 16 evaluable patients showed improvement of pancytopenia and decrease in the marrow blast count, although cheilitis and hyperkeratosis were observed in nearly all patients. Other differentiation inducers, such as butyrate 2~9 and alkyl lysophospholipid, 2'~ were administered to patients with acute myelogenous leukemia that was refractory to conventional chemotherapeutic drugs and found to cause increase in mature myeloid cells in the peripheral blood of the patients. Some clinical improvements were also observed in patients given butyrate. ~39However, it is unknown whether the mature cells that increased were derived directly from the immature leukemic cells. On the other hand, several cancer chemotherapeutic drugs with ability to induce in vitro differentiation of myeloid leukemia cells were suggested to exert their antileukemic effect by in vivo induction of differentiation of the leukemic cells. Treatments of patients with acute nonlymphocytic leukemia that was refractory to conventional chemotherapy with low doses of either Ara C or aclacinomycin A for relatively long periods resulted in increase in mature granulocytes in the peripheral blood with some clinical improvements. 24~-245Several cases of refractory anemia with an excess of blasts (RAEB) were also found to show improvement on this Ara C treatment. ~" Recently, Boyd and Sullivan 2~6 reported that the antileukemic drug harringtonine induced in vivo and in vitro differentiation of acute nonlymphocytic leukemia cells and suggested that the antileukemic effect of harringtonine was due to its ability to induce differentiation of leukemia cells. VII. C O N C L U D I N G R E M A R K S With the development of methods for long-term in vitro culture of normal hematopoietic progenitor ceils, recent studies on factors affecting growth and differentiation of the progenitor cells have shown that there were successive changes in response of the progenitor cells to these factors during leukemogenic transformation.'-3s Although growth of the hematopoietic progenitor cells was initially dependent on certain growth factors, the cells later became independent of these factors through autogenous production of their own, and developed to have a leukemogenic potential in syngeneic animals. ~Fhesechanges in responses of the progenitor cells to factors affecting growth and differentiation were also examined and confirmed with several preleukemic hematopoietic progenitor cells or cell lines that were either dependent on or independent of growth factors. ''Js Although growth of the hematopoietic progenitor cell line and preleukemic cell lines was stimulated by various growth factors, IL-3 was found to be important in regulation of the cell lines. 8,~'-19 However, details of the mechanisms of actions of IL-3 in stimulating proliferation of the hematopoietic progenitor cells or cell lines remain to be examined. Numerous growth factor-dependent or-independent hematopoietic progenitor cell lines were derived from retrovirus-infected bone marrow cultures and the virus was suggested to be involved in the mechanisms of development of the cell lines or the leukemogenic process of the cells, l~.a~There is also evidence that virus infection causes changes in control of growth and differentiation of hematopoietic progenitor cells into those of leukemic cells, t~.2~ The proliferations of several leukemia cell lines are dependent on certain growth factors, including TCGF (IL-2)fl .L~ IL-3, tg LPGF, 2s or tumor promoters, 26 but this dependence on the growth factors may not be essential for leukemogenesis. However, autostimulation of growth of leukemic cells by autogenously produced growth factor is suggested to be one of the many alterations in phenotypes of leukemia cells giving

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these cells a selective advantage for in vitro growth. 9.j~ Although the mechanisms of stimulation of proliferation of growth factor-dependent leukemia cell lines by various growth factors remain to be investigated, the mechanisms of promotion of growth by tumor promoters in a tumor promoter-dependent mouse leukemia cell line (A65T) are suggested to be different from those of other growth factors such as IL-2 and IL-3. 2'~ This A65T celI line responded to promoters of mouse skin tumorigenesis, but not to other growth factors. It remains to be investigated, however, whether skin tumor promoters can promote in vivo leukemogenesis of this type of thymic leukemia. Although various marker profiles of numerous established human leukemia cell lines were heterogeneous, each cell line was suggested to be at a particular stage of lymphoid, myeloid, or erythroid differentiation in development from a single pluripotent stem cell. ~a On the other hand, growth and differentiation of various leukemia cell lines have been shown to be affected by various compounds, s222~ Evidence is also accumulating to show that fresh human leukemic cells in primary culture and some myeloid leukemia cells in vivo in experimental animals or leukemic patients respond to various inducers of differentiation and differentiate to more mature cells, s4.56-5~,2'4"23~ These results suggest that some leukemic cells can be formed by impairment of a certain stage of development of the normal hematopoietic process. Various physiological and nonphysiological compounds 52-~2~have been found to affect differentiation of leukemia cells, but details of the mechanisms of induction of differentiation of most of the leukemia cells await further investigations. Among the leukemia cell lines examined, some murine and human myeloid leukemia cell lines were shown to be induced to differentiate into macrophage- or granulocyte-like cells by protein inducers (D-factor) which were related to CSF. 52-9~ However, recent purification and characterization of these factors showed that most of the D-factor activities ior myeloid leukemia cell lines (MI, WEHI-3B, and HL-60) are distinct from most of ttle CSF activities and other lymphokine activities. ~-gL In mice, D-factor without CSF activity is suggested to regulate a late stage of differentiation of normal hematopoiesis, while CSF without D-factor activity stimulates growth and differentiation of early stages of differentiation of normal progenitor cells of macrophages and granulocytes?'." Since D-factor can be produced by differentiating normal hematopoietic progenitor cells, mechanisms may exist for coupling growth and differentiation in the differentiating normal progenitor cells. ~''s9"9~ This coupling is suggested to be deficient in leukemic cells. 54,a9-9' This difference in molecular control mechanisms between normal hematopoietic progenitor cells and leukemic cells remains to be investigated. Various m yeloid leukemia cell lines do not respond to the D-factors, but respond to other physiological or nonphysiological compounds (Tables 4 and 5). Results of studies on the mechanisms of induction of differentiation of leukemia cells by these compounds suggest that modifications of cellular components in the membrane or nucleus are closely associated with differentiation of the cells and that these modifications are involved in the mechanisms of induction of differentiation of the cells. 57,5a.~6-2~ Detailed mechanisms of induction of differentiation, however, require further investigation. Recently, it has been shown that expression of several cellular oncogenes (myb, myc, and fes) that are homologous to the oncogenes of tumorigenic retroviruses is reduced in differentiating rayeloid leukemia cell lines, and this suppression of the expression of oncogenes is suggested to be involved in the mechanisms of differentiation of the cells. 2~ Phenotypic changes of HL--60 cells associated with differentiation by I a,25dihydroxyvitamin D3 were preceded by marked reduction in expression of the myr gene, T M while expression of the myc gene was recently shown to be inversely correlated with the state of differentiation of the cells, irrespective of the nature of the inducer or the rate of cell proliferation. 2~2o2" However, the detailed molecular mechanisms of

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changes in control of expression of the oncogenes during induction of differentiation of the leukemia cells and during leukemogenic changes in hematopoietic progenitor cells are unknown,. Several murine myeloid leukemia cell lines can be induced io differentiate in vivo by inducers of in vitro differentiation of the leukemia cell Jines, s'.s6''.2''-22~ and the survivals of animals inoculated with some leukemia cell lines were markedly prolonged by administration of the differentiation inducers, s4's6-ss'2''22~ These results show that in vivo induction of differentiation of the leukemia cells is a potential method for control of leul~emia. Recently, fresh human leukemia cells in primary culture were found to be induced to differentiate into mature cells by various inducers of established leukemia cell lines, and therapeutic improvements were observed in patients with myeloid leukemia on treatment with some differentiation inducers, s''ssJ6'.66,22'-~'o Further studies are necessary on factors modifying in vivo induction of differentiation of leukemia cells. Thus, established leukemia cell lines have contributed greatly to the understanding and control of proliferation and differentiation of leukemia cells and these cell lines will also be useful for further studies on the detailed characterization and control of leukemia cells. However, it should be noted that during establishment of the leukemia cell lines, the characteristics of the original leukemia cells may change. Therefore, the in vivo and therapeutic significance of results obtained with established leukemia cell lines should be carefully evaluated. ACKNOWLEDGMENTS The author isgrateful to Drs. Yoshio Honma, Mikio Tomida, and Moriaki Hayashi in the Department of Chemotherapy, Saitama Cancer Center Research Institute, for their critical reading of the manuscript, The work of our group cited was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science and Culture and from the Ministry of Health and Welfare for a Comprehensive 10Year Strategy for Cancer Control, Japan.

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10. Salahuddin, S. Z., Markham, P. D., Lindner, S. G., Gootenberg, J., Popovic, M., Hemmi, H., Sarin, P. S., and Gallo, R. C., Lymphokine production by cultured human T ceils transformed by human T-cell leukemia-lymphoma virus.l, Science, 223,703, 1984. 11. Greenberger, J, S., Humphries, K., Sakakeeny, M. A., Eckner, R. J., Ihle, J., Eaves, C., Cantor, H., Denberg, J., and Nabel, G., Demonstration of a permanent line of self-renewing multipotential hematopoietic stem cells in vitro, Blood, 58 (Suppl. 1), 97, 1981. 12. Dexter, T. M.~ Garland, .l., Scott, D., Scolnick, E., and Metcalf, D., Growth of factor-dependent hematopoietic precursor cell tines, J. Exp. Med., I52, 1036, I980. 13. Nagao, K., Yokoro, K., and Aaronson, S. A., Continuous lines of basophil/mast cells derived from normal mouse bone marrow, Science, 212, 333, 1981. 14. Nabel, G., Galli, S. J., Dvorak, A. M., Dvorak, H. 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J., Sakakeeny, M., Marks, P., Reid, D., Nabel, G., Hapel, A., lhle, J. N., and Humphries, K. C., Interleukin 3-dependent hematopoietic progenitor cell lines, Fed. Proc., 42, 2762, 1983. 20. Greenberger, J. S., Hapel, A., Nabel, G., Eckner, g. J., Newburger, P. E., lhle, J., Denburg, J., Moloney, W. C., Sakakeeny, M. A., and Humphries, K., Effect of rnurine leukemia viruses on establishment, growth and differentiation of permanent factor-dependent committed and pluripotential hematopoietic stern cell lines in vitro, in Yearbook of Experimental Hematology, Baum, S. J., Ed., S. Karger, New York, 1982, 195. 21. Ihle, J. N., Keller, J., Oroszlan, S., Henderson, L. E., Copeland, T. D., Fitch, F., Prystowsky, M. 1~,, Goldwasser, E., Schrader, J, W., Palaszynski, E., D~, M., and Lebel, B., Biologic properties of homogeneous interleukin 3. [. 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32. Miyazaw~., T., Sato, C., Hiai, H., Nishi, Y., and Matsuyama, M., Establishment of a reticuloepithelial-like cell line from mouse thymuses and its feeder capacity for growth of bone marrow cells. Cell Struct. Funct., 5,305, 1980. 33. Hiai, H., Nishi, Y., Miyazawa, T., Matsudaira, Y., and Nishizuka, Y., Mouse lymphoid teukemias: symbiotic complexes of neoplastic lymphocytes and their microenvironments, J. Natl. Cancer Inst., 66, 713, 1981. 34. Hiai, H. and Nishizuka, Y,, Growth stimulation of microenvironment-dependent mouse leukemias by tumor-promoting phorbol esters, J. Natl. Cancer Inst,, 67, 1333, 1981. 35. Hiai, H., Shisa, H., Nishi, Y., lnoue, Y., lkawa, Y., Matsudaira, Y., and Nishizuka, Y.~ Symbiotic culture of mouse leukaemias: regulation of cell interaction by an activity of serum, Virchows Arch. B CellPathoL, 32, 261, 1980. 36. Pulfertaft, R. J., Cytology of Burkitts' tumor (African lymphoma), Lancet, I, 238, 1964. 37. Minowada, J., Ohnuma, T., and Moore, G. E., Rosette-forming human lymphoid cell lines. I. Establishment and evidence for origin of thymus-derived lymphocytes, 3. Natl. Cancer Inst., 49, 891, 1972. 38. Minowada, J., Immunology of leukemia, in lmmunoloby of Leukemic Cells, Gunz, F. and Hender.. son, E., Eds., Grune & Stratton, New York, 1982, 119. 39. Minowada, J., Sagawa, K., Lok, M. S., Kubonishi, 1., Nakazawa, S., Tatsumi, E., Ohnuma, T., and Goldblum, N., A model of lymphoid-myeloid cell differentiation based on the study of marker profiles of 50 human leukemia-lymphoma cell lines, in International Symposium on New Trends in Human Immunology and Cancer Immunotherapy, Serrou, B. and Rosenfeld, C., Eds., Ooin, Paris, 1980, 188. 40. Miyoshi, I., Kubonishi, I., Sumida, M., Yoshimoto, S., Hiraki, T., Tsubota, T., Kobashi, H., Lai, M., Tanaka, T., Kimura, I., Miyamoto, K., and Sato, J., Characteristics of a leukemic T.cell derived from adult T-cell leukemia, Jpn. J. Clin. Oncol., 9(Suppl. 1), 485, 1979. 4I. Kubonishi, I., Machida, K., Sonobe, H., Ohtsuki, Y., Akagi, T., and Miyoshi, 1., Two new human myeloid cell lines derived from acute promyelocytic leukemia and claronic myelocytic leukemia, Gann, 74, 319, 1983. 42. Kubonishi, 1., Maehida, K., Niiya, K., Sonobe, H., Ohtsuki, Y., lwata, K., and Miyoshi, 1., Establishment of a new peroxidase-positive human myeloid cell line, PL-21, Blood, 63,254, 1984. 43. Tsuchiya, S., Yamabe, M., Yamaguchi, Y., Kobayashi, Y., Kouno, T., and Tada, K., Establishment and characterization of a human acute monocytic leukemia cell line (THP-I), Int. J. Cancer, 26, 171, 1980. 44. Ralph, P., Williams, N., Moore, M. A. S., and Litcofsky, P. B., Induction of antibod~-depen6ent and nonspecific tumor killing in human monocytic leukemia cells by nonlymphocyte factors and phorbol ester, Cell. 1mmunol., 71,215, 1982. 45. Ben-Bassat, H., Korkesh, A., Voss, R., Leizerowitz, R., and Polliack, A,, Establishment and characterization of a new permanent cell line (GDM-I) from a patient with myelomonoblastic leukemia, Leukemia Res., 6, 743, ]982. 46. Martin, P. and Papayannopoulou, T., IdEL cells: a new human erythroleukemia cell line with spontaneous and induced globin expression, Science, 216, I233,1982. 47. Sundstrom, C. and Nilsson, K., Establishment and characterization of a human histiocytic lymphoma cell line (U-937), Int. J. Cancer, 17,565, 1976. 48. Borella, L. and Sen, L., T cell surface markers on lymphoblasts from acute leukemia, J. lmmunoL, 111, 1251, 1973. 49. Seligmann, M., Preud'Homme, J. L., and Brouet, J. C., B and T cell markers in human proliferative blood diseases and primary immunodeficiencies with special reference to membrane bound immunoglobulins, Transplant. Rev., 16, 163,1973. 50. Janossy, G., Greaves, M. F., Revesz, T., Lister, T. A., Roberts, M., Durrant, J., Kirk, B., Catovsky, D., and Beard, M. E. J., Blast crisis of chronic myeloid leukaemia (CML). II. Cell surface marker analysis of "lymphoid" and myeloid cases, Br. J. Haematoi., 34, 179, 1976. 51. Arya, S. K., Wong-Staai, F., and Gallo, R. C., T-cell growth factor gene: lack of expression in human T-cell leukemia-lymphoma virus-infected cells, Science,223, 1086, 1984. 52. Ichikawa, Y., Differentiation of a cell line of myeloid leukemia, J. Cell. Physiol., 74, 223,1969. 53. Sachs, L., Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukemia, Nature (London), 274, 535, 1978. 54. Sachs, L., Control of growth and normal differentiation in leukemic cells: regulation of the developmental program and restoration of the normal phenotype in myeloid leukemia, J. Cell. PhysioL, Suppl. 1,151, 1982. 55. Hozumi, M., Umezawa, T., Takenaga, K., Ohno, T., Shikita, M., and u I., Characterization of factors stimulating differentiation of myeloid leukemia cells from a u sarcoma cell line cultured in serum-free medium, Cancer Res., 39, 5127,1979.

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