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The common acute lymphoblastic leukemia antigen (Neutral endopeptidase-3.4.24.11) gene is located on human chromosome 3
The Common Acute Lymphoblastic Leukemia Antigen (Neutral Endopeptidase-3.4.24.11) Gene is Located on Human Chromosome 3 Rosette Tran-Paterson, Huntington F. Willard, and Michelle Letarte
ABSTRACT: We have previously isolated a cDNA clone encoding the common acute lymphoblastic leukemia antigen (CALLA) from a normal human kidney library. Analysis of the amino acid sequence deduced from nucleotide sequencing of this cDNA established that CALLA is identical to the recently cloned human neutral endopeptidase (NEP; E.C. 3.4.24.11). Southern blot analysis of SacI fragments of DNA from human-rodent somatic cell hybrids using a 1.6-kb CALLA cDNA probe showed that the CALLA-NEP gene is located on human chromosome 3. The c o m m o n acute lymphoblastic leukemia antigen (CALLA) is a glycoprotein of molecular weight 100,000 associated with 85% of cases of childhood acute lymphoblastic leukemia (ALL), those with the non-T ALL phenotype [1, 2]. It is probably the best diagnostic marker of non-T ALL, being absent from normal peripheral blood mononuclear cells. CALLA is also present on Burkitt l y m p h o m a and follicular lymphoma [3], melanoma [4], and glioma ceils [5]. It is also expressed on lymphoid precursors in fetal liver and bone marrow [6], but not on mature B and T cells, suggesting that the antigen may play a role in the early steps of lymphoid differentiation. In normal nonlymphoid tissues, CALLA is particularly abundant on the brush border of the kidney [7, 8]. We have previously described the isolation and characterization of a CALLAspecific cDNA (clone 45) from a h u m a n kidney library using oligonucleotide probes [9]. The deduced amino acid sequence, composed of 749 residues, was found to be identical to that derived from a CALLA cDNA isolated from the Nalm-6 leukemic cell line [9, 10] and also to that of h u m a n neutral endopeptidase (NEP; EC 3.4.24.11) [11]. This enzyme, also referred to as enkephalinase [12], is a zinc-binding metallopeptidase that can inactivate several peptides including enkephalins, neurotensin, angiotensins, substance P, oxytocin, chemotactic peptide, and natriuretic peptide, by cleavage at the amino side of hydrophobic residues [13-16]. Nucleotide sequencing of the full-length CALLA cDNA clone 45 has been completed and is illustrated in Figure 1. The cDNA is 2998 bp long, including 139 bp of 5' untranslated region, an open reading frame of 2247 bp, and 612 bp of 3' untransFrom the Department of Immunology,Hospital for Sick Children (R. T-P., M. L.) and the Department of Medical Genetics (H. F. W.), University of Toronto, Canada. Address reprint requests to: M. Letarte, Department of Immunology, Hospital for Sick Children, 555 University Avenue, Toronto, Canada M5G 1X8. Received December 6, 1988; accepted April 18, 1989.
129 © 1989 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet42:129-134 (1989]
0165-4608/89/$03.50
130
R. Tran-Paterson et al. CALLA cDNA clone 45:
-139
570 627 EE IL,
E I
2208 2307 EE I I
2737 E I AAAAA
ORF
Figure 1 Schematic representation of CALLA cDNA clone 45. The CALLA cDNA clone 45 isolated from a human kidney library contains six EcoRI sites (E), positioned at bp-139, 570, 627, 2208, 2307, and 2737. Upstream from the open reading frame (ORF) of 2247 bp is a 139-bp sequence of 5' untranslated region [shown with negative numbers). The cDNA ends by a poiyA tail at bp 2859. The fragment of 1581 bp (627-2208), highlighted in the diagram, is used as
hybridization probe in Figure 2.
lated region. The 1581 bp EcoRI fragment (Fig. 1) was used as hybridization probe in southern blot analysis of DNA extracted from 11 human-mouse and four h u m a n hamster hybrid cell lines characterized previously [17, 18]. The DNA was digested with SacI and subjected to gel electrophoresis and southern blot analysis [19, 20]. In human genomic DNA, the CALLA probe detects four major SacI bands of 22, 9.5, 3.9, and 3.8 kb and one minor band of 5 kb (Fig. 2, lane 1). This human probe hybridizes to two homologous bands of 23 and 18 kb in mouse DNA (Fig. 2, lane 6} and to three bands of 23, 12, and 6.5 kb in hamster DNA (data not shown). Three of the human bands (22, 3.9, and 3.8 kb) segregated with a 100% concordancy in the 15 human-rodent hybrids tested (Table 1) and could be assigned to chromosome 3. All other chromosomes were discordant in at least four hybrids (Table 1). The pattern of hybridization of DNA from three human-mouse hybrids reactive with the CALLA probe is shown in Figure 2 (lanes 2-4). The assignment of the gene to chromosome 3 was further confirmed by hybridization of the SacI fragments of 22, 3.9, and 3.8 kb with the CALLA probe, in a human-mouse hybrid cell line containing only the human chromosome 3 (Fig. 2, lane 4) [21]. In the positive hybrids, the human SacI fragments of 9.5 and 5.0 kb were less well resolved than the 22-, 3.9-, and 3.8-kb fragments (Fig. 2, lanes 2-4). This could be explained, particularly in the case of the 5.0-kb band, by a lower intensity in human DNA (Fig. 2, lane 1). The 9.5- and 5.0-kb
I 22~ 9.5
5.Ore
3.9m 3.8~
2
3
4
5
6
Figure 2 Hybridization of the human CALLA-NEPprobe to SacI fragments of DNA from human-mouse hybrids. DNA samples {10-15 /~g} prepared from human cells {lane 1), mouse cells {lane 6), and human-mouse hybrid cells {lanes 2-5) were digested with SacI and subjected to electrophoresis. Southern blot analysis was performed with the 1581-bp EcoRI fragment of CALLAcDNA clone 45 (Fig. 1}, which was labeled with [azP]a dCTP by random primer and hybridized to filters using standard conditions. The filters were washed under stringent conditions (0.1 XSCC;0.5% SDS, at 65°C) and exposed for 18 hours.
°
--
Chromosome
2
3
59
1 6 7
4
6
7
8
9
with human
10
11
47
1
4
12 5
14 2 2 5 5
16
6 1 1 7 2 7 7 27 54 40 40
3 2
13
15
18 2 1 5 6 3 4 5 4 55 67
17
in somatic cell hybrids a
Human chromosome
chromosomes
3 2 2 3 1 2 4 3 4 5 5 4 6 5 3 4 3 2 5 4 2 3 3 3 5 6 3 4 6 5 5 5 47 47 67 53 53 53 40
5
sequences
The number of hybrid cells DNA tested was 15.
Mouse-human and hamster-human hybrids.
3 1 7 4 60 2 4 0 6 4 8 1 40 45 0
1
S e g r e g a t i o n of N E P - C A L L A
+ -+ -Percent d i s c o r d a n c yb
+ + -
Gene
Table I
3 4 4 4 55
19
3 4 2 6 40
20
5 2 7 1 60
21
3 4 2 6 40
22
6 l 8 0 60
X
1 6 0 8 40
Y
13 2
R. Tran-Paterson et al. bands could also represent nonfunctional CALLA-NEP pseudogenes, or genes crosshybridizing with the CALLA-NEP probe. The restriction m a p of CALLA-NEP at the genomic level, w h i c h is not available yet, should allow us to determine w h e t h e r these two fragments are an integral part of the gene. Genes previously assigned to c h r o m o s o m e 3 encode for p o l y p e p t i d e h o r m o n e s or their receptors such as the thyroid h o r m o n e receptor, lactoferrin, transferrin and transferrin receptor, somatostatin, and for enzymes such as ~-galactosidase, acetylcholinesterase, p r o p i o n y l CoA carboxylase, and d e l t a - a m i n o l e v u l i n a t e synthetase [22]. Thus, neutral e n d o p e p t i d a s e 24.11 (CALLA-NEP) represents an a d d i t i o n a l enzyme m a p p i n g to c h r o m o s o m e 3. The c-rafol and the c-erb-A-B oncogenes have also been localized to 3p25 and 3p22-24.1 regions, respectively [22]. The regional localization of the CALLA-NEP gene should establish its position relative to these other genes and provide useful information in the construction of the physical m a p of c h r o m o s o m e 3. Alterations of c h r o m o s o m e 3 have been reported for several malignancies. Deletions and translocations of this c h r o m o s o m e are frequent in small cell lung carcinoma, ovarian, breast, and renal cell carcinoma [23-25]. Translocations of chromosome 3 have been reported in hematologic malignancies such as acute n o n l y m p h o c y t i c leukemia [26], malignant l y m p h o m a [27], and cutaneous T-cell l y m p h a m a [28]. In non-T ALL, translocations involving c h r o m o s o m e 3 have been observed in a few cases but do not represent a c o m m o n feature of this disease [29]. The presence of CALLA-NEP in several tissues i n c l u d i n g kidney, lung, brain, intestine, and breast [7, 12, 30, 31] suggests that it m a y be present in malignancies of the corresponding tissues. The availability of the m o l e c u l a r probes for CALLA-NEP will allow us to look for the expression of this gene in neoplasias other than leukemia. Analysis of the CALLA-NEP gene in normal and t u m o r cells m a y reveal structural alterations on c h r o m o s o m e 3 associated with a specific malignancy.
Note Added in Proof Following submission of this m a n u s c r i p t on December 6, 1988, an i n d e p e n d e n t report has confirmed the localization of CALLA to c h r o m o s o m e 3 [32]. The report describes the m a p p i n g of the CALLA gene to the c h r o m o s o m a l region 3(q21-27). This research was supported in part by grants (to M. L.) from the National Cancer Institute and the Medical Research Council of Canada. M. L. is a Terry Fox Research Scientist of the National Cancer Institute. The authors thank Sonia Vera and Russell J. Onizuka far their assistance in generating the molecular probe and Anne-Marie Lamhonwah for her critical reading of the manuscript.
REFERENCES 1. Bernard A, Boumsell L, Dausset J, Milstein C, Schlossman SF (1984): Leukocyte Typing. Springer Verlag, Berlin. 2. Foon KA, Todd RF (1986): Immunologic classification of leukemia and lymphoma. Blood 68:1-31. 3. Ritz J, Nadler LM, Bhan AK, Notis-McConarty J, Pesando JM, Schlossman SF (1981): Expression of common acute lymphoblastic leukemia antigen (CALLA) by lymphomas of Bcell and T-cell lineage. Blood 58:648-652. 4. Carrel S, Schmidt-Kessen A, Mach JP, Heumann D, Girardet C (1983): Expression of common acute lymphoblastic leukemia antigens (CALLA) on human malignant melanoma cells. J Immunol 130:2456-2460. 5. Carrel S, de Tribolet N, Gross N (1982): Expression of HLA-DR and common acute lymphoblastic leukemia antigen on glioma cells. Eur J lmmunol 12:354-357.
C h r o m o s o m e Mapping of the CALLA-NEP Gene
133
6. Hokland P, Rosenthal P, Griffin JD, Nadler LM, Daley J, Hokland M, Schlossman SF, Ritz J (1983): Purification and characterization of fetal hematopoietic cells that express the common acute lymphoblastic leukemia antigen (CALLA). J Exp Med 157:114-129. 7. Metzgar RS, Borowitz MJ, Jones NH, Dowell BR (1981): Distribution of common acute lymphoblastic leukemia antigen in nonhematopoietic tissues. J Exp Med 154:1249-1254. 8. Quackenbush EJ, Gougos A, Baumal R, Letarte M (1986): Differential localization within human kidney of five membrane proteins expressed on acute lymphoblastic leukemia cells. ] lmmunol 136:118-124. 9. Letarte M, Vera S, Tran R, Addis JBL, Onizuka RJ, Quackenbush EJ, Jongeneel CV, Mclnnes RR (1988): Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase. J Exp Med 168:1247-1253. 10. Shipp MA, Richardson NE, Sayre PH, Brown NR, Masteller EL, Clayton LK, Ritz J, Reinherz EL (1988): Molecular cloning of the common acute lymphoblastic leukemia antigen (CALLA) identifies a type II integral membrane protein. Proc Natl Acad Sci USA 85:48194823. 11. Malfroy B, Kuang WJ, Seeburg PH, Mason AJ, Schofield PR (1988): Molecular cloning and amino acid sequence of human enkephalinase (neutral endopeptidase). FEBS Lett 229:206210. 12. Relton JM, Gee NS, Matsas R, Turner AJ, Kenny AJ (1983): Purification of endopeptidase24.11 ("enkephalinase") from pig brain by immunoadsorbent chromatography. Biochem J 215:519-523. 13. Kerr MA, Kenny AJ (1974): The purification and specificity of a neutral endopeptidase from rabbit kidney brush border. Biochem J 137:477-488. 14. Gafford JT, Skidgel EG, Erdos EG, Hersh LB (1983): Human kidney "enkephalinase," a neutral metalloendopeptidase that cleaves active peptides. Biochemistry 22:3265-3271. 15. Connelly JC, Skidgel RA, Schulz WW, Johnson AR, Erdos EG (1985): Neutral endopeptidase-24.11 in human neutrophils: Cleavage of chemotactic peptide. Proc Natl Acad Sci USA 82:8737-8741. 16. Stephenson SL, Kenny AJ (1987): The hydrolysis of a-human atrial natriuretic peptide by pig kidney microvillar membranes is initiated by endopeptidase-24.11. Biochem J 243:183187. 17. Willard HF, Riordan JR (1985): Assignment of the gene for myelin proteolipid protein to the X chromosome: Implications for X-linked inherited myelin disorders. Science 230:940942. 18. Willard HF, Meakin SO, Tsui L-C, Breitman ML (1985): Assignment of the human gamma crystallin multigene family to chromosome 2. Somat Cell Mol Genet 11:511-516. 19. Maniatis T, Fritsch EF, Sambrook J (1982): Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, pp. 382-386. 20. Southern EM (1975): Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:502-517. 21. Willard HF (1985): Chromosome-specific organization of human alpha satellite DNA. Am J Hum Genet 37:524-532. 22. Pearson PL, Kidd KK, Willard HF, et al. (1987): Report of the committee on human gene mapping by recombinant DNA techniques. Ninth International Workshop in Human Gene Mapping. Cytogenet Cell Genet 46:390-566. 23. Bloomfield CD, Trent JM, Van Den Berghe H (1987): Report of the Committee on Structural Chromosome Changes in Human Neoplasia. Ninth International Workshop in Human Gene Mapping. Cytogenet Cell Genet 46:344-366. 24. Drabkin HA, Bradley C, Hart I, Bleskan J, Li FP, Patterson D (1985): Translocation of c-myc in the hereditary renal cell carcinoma associated with t(3;8)(p14.2;q24.13) chromosomal translocation. Proc Natl Acad Sci USA 82:6980-6984. 25. Wurster-Hill DH, Cannizzaro LA, Pettengill OS, Sorenson GD, Cate CC, Maurer LH (1984): Cytogenetics of small cell carcinoma of the lung. Cancer Genet Cytogenet 13:303-330. 26. Bitter MA, Neilly ME, Lebeau MM, Pearson MJG, Rowley JD (1985): Rearrangements of chromosome 3 involving bands 3q21 and 3q26 are associated with normal or elevated platelet counts in acute non-lymphocytic leukemia. Blood 66:1362-1370. 27. Bloomfield CD, Arthur DC, Frizzera G, Levine EG, Peterson BA, Gajl-Peczalska KJ (1983): Non-random chromosome abnormalities in lymphoma. Cancer Res 43:2975-2984.
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28. Whang-Peng J, Bunn PA, Knutsen T, Matthews MJ, Schechter G, Minna JD (1982): Clinical implications of cytogenetic studies in cutaneous T-cell lymphoma (CTCL). Cancer 50:1539-1553. 29. Williams DL, Look AT, Melvin SL, Roberson PK, Dahl G, Flake T, Stass S (1984): New chromosomal translocations correlate with specific immunophenotypes of childhood acute lymphoblastic leukemia. Cell 36:101-109. 30. Tredjdosiewicz LK, Malizia G, Oakes J, Losowsky MS, Janossy G (1985): Expression of the common acute lymphoblastic leukemia antigen (CALLA gpl00) in the brush border of the normal jejunum and jejunum of patients with coeliac disease. J Clin Pathol 38:1002-1006. 31. Gusterson BA, Monaghan P, Mahedran R, Ellis J, O'Hare MJ (1986): Identification of myoepithelial cells in human and rat breasts by anti-common acute lymphoblastic leukemia antigen antibody A12. J Natl Cancer Inst 77:343-347. 32. Barker PE, Shipp MA, D'Adamio L, Masteller EL, Reinherz EL (1989): The common acute lymphoblastic leukemia antigen gene maps to chromosomal region 3(q21-27). J Immunol 142:283-287.
ABSTRACT: We have previously isolated a cDNA clone encoding the common acute lymphoblastic leukemia antigen (CALLA) from a normal human kidney library. Analysis of the amino acid sequence deduced from nucleotide sequencing of this cDNA established that CALLA is identical to the recently cloned human neutral endopeptidase (NEP; E.C. 3.4.24.11). Southern blot analysis of SacI fragments of DNA from human-rodent somatic cell hybrids using a 1.6-kb CALLA cDNA probe showed that the CALLA-NEP gene is located on human chromosome 3. The c o m m o n acute lymphoblastic leukemia antigen (CALLA) is a glycoprotein of molecular weight 100,000 associated with 85% of cases of childhood acute lymphoblastic leukemia (ALL), those with the non-T ALL phenotype [1, 2]. It is probably the best diagnostic marker of non-T ALL, being absent from normal peripheral blood mononuclear cells. CALLA is also present on Burkitt l y m p h o m a and follicular lymphoma [3], melanoma [4], and glioma ceils [5]. It is also expressed on lymphoid precursors in fetal liver and bone marrow [6], but not on mature B and T cells, suggesting that the antigen may play a role in the early steps of lymphoid differentiation. In normal nonlymphoid tissues, CALLA is particularly abundant on the brush border of the kidney [7, 8]. We have previously described the isolation and characterization of a CALLAspecific cDNA (clone 45) from a h u m a n kidney library using oligonucleotide probes [9]. The deduced amino acid sequence, composed of 749 residues, was found to be identical to that derived from a CALLA cDNA isolated from the Nalm-6 leukemic cell line [9, 10] and also to that of h u m a n neutral endopeptidase (NEP; EC 3.4.24.11) [11]. This enzyme, also referred to as enkephalinase [12], is a zinc-binding metallopeptidase that can inactivate several peptides including enkephalins, neurotensin, angiotensins, substance P, oxytocin, chemotactic peptide, and natriuretic peptide, by cleavage at the amino side of hydrophobic residues [13-16]. Nucleotide sequencing of the full-length CALLA cDNA clone 45 has been completed and is illustrated in Figure 1. The cDNA is 2998 bp long, including 139 bp of 5' untranslated region, an open reading frame of 2247 bp, and 612 bp of 3' untransFrom the Department of Immunology,Hospital for Sick Children (R. T-P., M. L.) and the Department of Medical Genetics (H. F. W.), University of Toronto, Canada. Address reprint requests to: M. Letarte, Department of Immunology, Hospital for Sick Children, 555 University Avenue, Toronto, Canada M5G 1X8. Received December 6, 1988; accepted April 18, 1989.
129 © 1989 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet42:129-134 (1989]
0165-4608/89/$03.50
130
R. Tran-Paterson et al. CALLA cDNA clone 45:
-139
570 627 EE IL,
E I
2208 2307 EE I I
2737 E I AAAAA
ORF
Figure 1 Schematic representation of CALLA cDNA clone 45. The CALLA cDNA clone 45 isolated from a human kidney library contains six EcoRI sites (E), positioned at bp-139, 570, 627, 2208, 2307, and 2737. Upstream from the open reading frame (ORF) of 2247 bp is a 139-bp sequence of 5' untranslated region [shown with negative numbers). The cDNA ends by a poiyA tail at bp 2859. The fragment of 1581 bp (627-2208), highlighted in the diagram, is used as
hybridization probe in Figure 2.
lated region. The 1581 bp EcoRI fragment (Fig. 1) was used as hybridization probe in southern blot analysis of DNA extracted from 11 human-mouse and four h u m a n hamster hybrid cell lines characterized previously [17, 18]. The DNA was digested with SacI and subjected to gel electrophoresis and southern blot analysis [19, 20]. In human genomic DNA, the CALLA probe detects four major SacI bands of 22, 9.5, 3.9, and 3.8 kb and one minor band of 5 kb (Fig. 2, lane 1). This human probe hybridizes to two homologous bands of 23 and 18 kb in mouse DNA (Fig. 2, lane 6} and to three bands of 23, 12, and 6.5 kb in hamster DNA (data not shown). Three of the human bands (22, 3.9, and 3.8 kb) segregated with a 100% concordancy in the 15 human-rodent hybrids tested (Table 1) and could be assigned to chromosome 3. All other chromosomes were discordant in at least four hybrids (Table 1). The pattern of hybridization of DNA from three human-mouse hybrids reactive with the CALLA probe is shown in Figure 2 (lanes 2-4). The assignment of the gene to chromosome 3 was further confirmed by hybridization of the SacI fragments of 22, 3.9, and 3.8 kb with the CALLA probe, in a human-mouse hybrid cell line containing only the human chromosome 3 (Fig. 2, lane 4) [21]. In the positive hybrids, the human SacI fragments of 9.5 and 5.0 kb were less well resolved than the 22-, 3.9-, and 3.8-kb fragments (Fig. 2, lanes 2-4). This could be explained, particularly in the case of the 5.0-kb band, by a lower intensity in human DNA (Fig. 2, lane 1). The 9.5- and 5.0-kb
I 22~ 9.5
5.Ore
3.9m 3.8~
2
3
4
5
6
Figure 2 Hybridization of the human CALLA-NEPprobe to SacI fragments of DNA from human-mouse hybrids. DNA samples {10-15 /~g} prepared from human cells {lane 1), mouse cells {lane 6), and human-mouse hybrid cells {lanes 2-5) were digested with SacI and subjected to electrophoresis. Southern blot analysis was performed with the 1581-bp EcoRI fragment of CALLAcDNA clone 45 (Fig. 1}, which was labeled with [azP]a dCTP by random primer and hybridized to filters using standard conditions. The filters were washed under stringent conditions (0.1 XSCC;0.5% SDS, at 65°C) and exposed for 18 hours.
°
--
Chromosome
2
3
59
1 6 7
4
6
7
8
9
with human
10
11
47
1
4
12 5
14 2 2 5 5
16
6 1 1 7 2 7 7 27 54 40 40
3 2
13
15
18 2 1 5 6 3 4 5 4 55 67
17
in somatic cell hybrids a
Human chromosome
chromosomes
3 2 2 3 1 2 4 3 4 5 5 4 6 5 3 4 3 2 5 4 2 3 3 3 5 6 3 4 6 5 5 5 47 47 67 53 53 53 40
5
sequences
The number of hybrid cells DNA tested was 15.
Mouse-human and hamster-human hybrids.
3 1 7 4 60 2 4 0 6 4 8 1 40 45 0
1
S e g r e g a t i o n of N E P - C A L L A
+ -+ -Percent d i s c o r d a n c yb
+ + -
Gene
Table I
3 4 4 4 55
19
3 4 2 6 40
20
5 2 7 1 60
21
3 4 2 6 40
22
6 l 8 0 60
X
1 6 0 8 40
Y
13 2
R. Tran-Paterson et al. bands could also represent nonfunctional CALLA-NEP pseudogenes, or genes crosshybridizing with the CALLA-NEP probe. The restriction m a p of CALLA-NEP at the genomic level, w h i c h is not available yet, should allow us to determine w h e t h e r these two fragments are an integral part of the gene. Genes previously assigned to c h r o m o s o m e 3 encode for p o l y p e p t i d e h o r m o n e s or their receptors such as the thyroid h o r m o n e receptor, lactoferrin, transferrin and transferrin receptor, somatostatin, and for enzymes such as ~-galactosidase, acetylcholinesterase, p r o p i o n y l CoA carboxylase, and d e l t a - a m i n o l e v u l i n a t e synthetase [22]. Thus, neutral e n d o p e p t i d a s e 24.11 (CALLA-NEP) represents an a d d i t i o n a l enzyme m a p p i n g to c h r o m o s o m e 3. The c-rafol and the c-erb-A-B oncogenes have also been localized to 3p25 and 3p22-24.1 regions, respectively [22]. The regional localization of the CALLA-NEP gene should establish its position relative to these other genes and provide useful information in the construction of the physical m a p of c h r o m o s o m e 3. Alterations of c h r o m o s o m e 3 have been reported for several malignancies. Deletions and translocations of this c h r o m o s o m e are frequent in small cell lung carcinoma, ovarian, breast, and renal cell carcinoma [23-25]. Translocations of chromosome 3 have been reported in hematologic malignancies such as acute n o n l y m p h o c y t i c leukemia [26], malignant l y m p h o m a [27], and cutaneous T-cell l y m p h a m a [28]. In non-T ALL, translocations involving c h r o m o s o m e 3 have been observed in a few cases but do not represent a c o m m o n feature of this disease [29]. The presence of CALLA-NEP in several tissues i n c l u d i n g kidney, lung, brain, intestine, and breast [7, 12, 30, 31] suggests that it m a y be present in malignancies of the corresponding tissues. The availability of the m o l e c u l a r probes for CALLA-NEP will allow us to look for the expression of this gene in neoplasias other than leukemia. Analysis of the CALLA-NEP gene in normal and t u m o r cells m a y reveal structural alterations on c h r o m o s o m e 3 associated with a specific malignancy.
Note Added in Proof Following submission of this m a n u s c r i p t on December 6, 1988, an i n d e p e n d e n t report has confirmed the localization of CALLA to c h r o m o s o m e 3 [32]. The report describes the m a p p i n g of the CALLA gene to the c h r o m o s o m a l region 3(q21-27). This research was supported in part by grants (to M. L.) from the National Cancer Institute and the Medical Research Council of Canada. M. L. is a Terry Fox Research Scientist of the National Cancer Institute. The authors thank Sonia Vera and Russell J. Onizuka far their assistance in generating the molecular probe and Anne-Marie Lamhonwah for her critical reading of the manuscript.
REFERENCES 1. Bernard A, Boumsell L, Dausset J, Milstein C, Schlossman SF (1984): Leukocyte Typing. Springer Verlag, Berlin. 2. Foon KA, Todd RF (1986): Immunologic classification of leukemia and lymphoma. Blood 68:1-31. 3. Ritz J, Nadler LM, Bhan AK, Notis-McConarty J, Pesando JM, Schlossman SF (1981): Expression of common acute lymphoblastic leukemia antigen (CALLA) by lymphomas of Bcell and T-cell lineage. Blood 58:648-652. 4. Carrel S, Schmidt-Kessen A, Mach JP, Heumann D, Girardet C (1983): Expression of common acute lymphoblastic leukemia antigens (CALLA) on human malignant melanoma cells. J Immunol 130:2456-2460. 5. Carrel S, de Tribolet N, Gross N (1982): Expression of HLA-DR and common acute lymphoblastic leukemia antigen on glioma cells. Eur J lmmunol 12:354-357.
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