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Translocation (2;7)(p13;q36) in a case of acute nonlymphocytic leukemia evolving from a myelodysplastic syndrome
Translocation (2;7)(p13;q36) in a Case of Acute Nonlymphocytic Leukemia Evolving from a Myelodysplastic Syndrome Chandrika Sreekantaiah, Maria R. Baer, Francesc So16, Harvey D. Preisler, and Avery A. Sandberg
A case of acute nonlymphocytic leukemia with a new translocation, t(2;7)(p13;q36), as the sole karyotypic abnormality is reported. The patient's leukemia evolved from a cytogenetically normal myelodysplastic syndrome of 4 years' duration. Following treatment the patient entered complete remission with loss of the cytogenetically abnormal clone. Subsequent bone marrow analyses showed recurrence of the myelodysplastic syndrome with a normal karyotype. Although both chromosomes 2 and 7 are known to be involved in nonrandom karyotypic changes in human cancer and leukemia, t(2;7)(p13;q36) has not been reported previously.
ABSTRACT:
INTRODUCTION Cytogenetic analyses of h u m a n leukemias performed using improved culture and b a n d i n g techniques indicate an increase from the previously reported 50% abnormalities in acute n o n l y m p h o c y t i c leukemia (ANLL) [1]. Many laboratories are currently finding that 70%-80% of patients have a cytogenetically abnormal clone, and Yunis et al. [2] have observed that approximately 90% of their cases have an abnormal karyotype. Several hematologic conditions, i n c l u d i n g preleukemias, are associated with abnormalities of chromosome 7 [3-5]. Reports of the specific involvement of chromosome 2 in aberrations are less c o m m o n [6]. We report herein an elderly patient with a translocation between chromosomes 2 and 7 with breaks at band 2p13, the region to which the transforming growth factor alpha (TGFA) [7, 8] and the c-re/ protooncogene [9] have been mapped, and band 7q36 to which the histone genes [10] have been localized. This finding is of great interest because molecular studies of cancer-associated chromosomal abnormalities indicate that such rearrangements may initiate transformation by activating cellular oncogenes and growth factor genes that lie w i t h i n or near the chromosomal breakpoints. The presence of these genes at the breakpoint in the t(2;7)(p13;q36) suggests m e c h a n i s m s by which the leukemic phenotype may have supervened in our patient. From the Departmentsof Geneticsand Endocrinology(C. S., F. S.) and HematologicOncology(M. R. B., H. D. P.), Roswell Park Memorial Institute, Buffalo. NY and the Genetics Center, Southwest Biomedical Research Institute, Scottsdale, AZ (A. A. S.). Address requests for reprints to Dr. Avery A. Sandberg, The Genetics Center, Southwest Biomedical Research Institute, 6401 E. Thomas Rd., Scottsdale, AZ 85251. Received April 11, 1988; accepted June 13, 1988.
199 c'. 1988 ElsevierScience PublishingCo.. Inc. 655 Avenueof the Americas,New York, NY 10010
Cancer Genet Cytogenel35:199 204 (1988) 0165-4608/88/$03.50
200
C. Sreekantaiah et al.
CASE REPORT
The patient is a 73-year-old white male, a retired politician without significant past medical or occupational history. He presented in 1983 at age 68 with a hemoglobin (Hb) of 10.7 g/dl, white blood cell count (WBC) 4600/mm 3 with 28% granulocytes, and platelet count 233,000/mm 3. Mean corpuscular volume was 104 fl, and reticulocyte count was 1%. Iron, B12, and folate levels were normal. The bone marrow was normocellular with a myeloid:erythroid ratio of 4:1, with 6% blasts and 9% promyelocytes. A diagnosis of myelodysplastic syndrome (MDS) was made. The patient's blood counts remained stable, and he required no therapeutic intervention until August 1987 when he presented with Hb 7.1 g/dl and WBC 16,O00/mm 3, with 20% blasts and 26% immature monocytes. Platelet count was 916,000/ram 3. Bone marrow cellularity was 50% with 47% blasts. Megaloblastic erythroid precursors were present, as were Pelger-Huet cells and dysplastic megakaryocytes. Auer rods were seen in the bone marrow blasts. Fifty-five percent of the bone marrow blasts stained with peroxidase, 55% with Sudan black, and 70% with nonspecific esterase. A diagnosis of acute myelogenous leukemia, FAB type M4, was made. The patient was treated with high-dose cytosine arabinoside and daunorubicin (September 1987) and achieved complete remission. In October 1987, the patient's Hb was 9.7 g/dl, WBC 5300/ram 3 with 31% granulocytes, and platelet count 435,000/mm 3. His bone marrow was hypocellular, with normal erythroid and myeloid precursors and megakaryocytes. He received one course of consolidation therapy with high-dose cytosine arabinoside and daunorubicin. Further consolidation therapy was not administered because of cardiac problems. He has not had a recurrence of the leukemia, but has developed recurrent anemia, necessitating red blood cell transfusions. Bone marrow analyses performed in December 1987 and January 1988 showed erythroid hypoplasia with megatobtastic changes, suggestive of recurrence of the MDS. CYTOGENETIC ANALYSIS Chromosomal studies were performed on short-term (48 hour) cultures of bone marrow samples using a high-resolution banding technique [11] with methotrexate synchronization. Slides prepared by an air-drying method were G banded with Wright stain [12] and/or stained using a combined G- and C-banding technique [13]. Karyotypes were expressed according to standard nomenclature [14]. The results of serial cytogenetic examinations of the bone marrow cells are shown in Table 1. The initial karyotypic analysis of the patient's bone marrow, at the time of diagnosis of MDS in 1983, revealed a normal karyotype. Chromosomal analysis done in 1987, when he was diagnosed as having ANLL-M4 showed a reciprocal translocation between chromosomes 2 and 7, t(2;7)(p13;q36), as the sole abnormality in all the cells analyzed (Fig. 1). Another pretreatment sample obtained 10 days later showed the same abnormality. One metaphase with a normal karyotype was seen. Subsequent analyses of bone marrow samples in remission and with recurrence of MDS all revealed normal karyotypes with total disappearance of the abnormal clone. DISCUSSION
Banding studies during the past decade have established correlations between specific chromosomal abnormalities and specific cancers and leukemias [2, 15]. In ANLL, morphologic subtypes have been shown to be associated with specific translocations and other changes [4, 16]. The MDS conditions, which progress to leuke-
(2;7)(p13:q36)
Table 1
201
Cytogenetic and clinical data on the bone marrow samples of the patient
Date of sampling
Diagnosis
Number of cells analyzed
Karyotype (Number of cells) 46,XY (27) 45,XY, random loss (3) 46,XY,t(2;7)(p13;q36) (15) 45,X,- Y,t(2;7)(p13;q36) (1) 46,XY,t(2;7)(p13;q36) (17) 46,XY (1) 46,XY (20)
7/21/83
MDS
30
9/1/87
AML pretreatment
16
9/11/87
AML pretreatment
18
10/23/87
AML remission, preconsolidation #1 Postconsolidation #1; recurrent MDS? MDS
20
12/21/87 1/19/88
22
46,XY (20) 45,XY, random loss (2)
20
46,XY (20)
mia in 10%-60% of cases [17], are also characterized by specific chromosomal defects, w h i c h generally resemble those seen in ANLL [5]. From molecular studies of specific translocations, it is apparent that the sites of consistent rearrangements specify c h r o m o s o m e segments that contain genes important in malignant transformation, specifically protooncogenes and other genetic loci for growth factors and growth factor receptors. Examples include the c - m y c translocations in Burkitt lymp h o m a {BL) [18] and the P h i l a d e l p h i a (Ph) translocation in chronic myeloblastic leukemia [19]. Our patient, who had no history of toxic exposure, was diagnosed as having MDS in 1983, at w h i c h time cytogenetic analysis revealed a normal karyotype. He presented in August 1987 with acute myeloblastic leukemia (AML), and this time karyotypic analysis revealed a t(2;7)(p13;q36). This translocation has not been reported previously. The breakpoints involved, 2p13 and 7q36, suggest m e c h a n i s m s whereby leukemic transformation may have occurred in this case. Abnormalities of c h r o m o s o m e 2 are seen infrequently in cancer i n c l u d i n g leukemia. The specific changes involving chromosome 2 include the variant t(2;8) in BL (eight cases described in [6]) and B-type acute l y m p h o c y t i c leukemia (B-ALL) (four cases described in [6]), and t(2;14) in chronic l y m p h o c y t i c leukemia (CLL) [20, 21]. The translocation breakpoint on chromosome 2, 2p13, in our case is of interest for a n u m b e r of reasons. Band 2p13 is a fragile site; fragile sites are k n o w n to have a significant correlation with the location of oncogenes and specific cancer c h r o m o s o m e breakpoints [22]. This band might thus exhibit a p r o p e n s i t y to be involved in cancer-associated translocations. It is interesting that 2p13 is near the region of breaks (2p11-p13) involved in various translocations; the t(2;8) in BL and p r e - B - and B-ALL [6], t(2;14) in B-CLL [20, 21], t(2;5) in a case of AML [23], and t(2;8) in m u l t i p l e m y e l o m a [24] and CLL [25]. Band 2p13 is the locus of the gene for the transforming growth factor alpha (TGFA) [7, 8]. The TGFA has been i m p l i c a t e d in tumor proliferation and cell transformation, perhaps by an autocrine feedback mechanism. Thus, a break in this region suggests that TGFA might have contributed to the leukemic progression in this case. The oncogene c-rel also has been localized to 2cen-2p13 [9], and a break in this
202
c. Sreekantaiah et al.
1
2
3
4
5
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7
13
14
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Figure 1 G-banded karyotype of the patient at the time of diagnosis of AML showing the t(2;7)(p13;q36) abnormality. region might result in its abnormal expression or overexpression, resulting in leukemic transformation. A n u m b e r of hematologic malignancies are frequently associated with aberrations of c h r o m o s o m e 7 [3-5] and our findings are consistent with this involvement. Secondary ANLL in particular is characterized by n o n r a n d o m changes either as - 7 or 7 q - . These patients generally have a history of exposure to toxic substances or radiation, including treatment for previous malignancy. Our patient was different in that he had no history of toxic exposure and the chromosomal aberration did not involve the loss of any part of chromosome 7, but instead was a translocation at the terminal band on the long arm, 7q36. The genes localized to this region are the Tcell receptor f3-chain gene [26-28], w h i c h has been postulated to be activated by translocations involving 7q32-36 in c h i l d h o o d T-ALL [29, 30] and the genes for histones [9]. The histone H3 gene has been demonstrated to be transcribed in normal as well as leukemic bone marrow [31]. All of the histone genes m a y in fact be expected to be undergoing transcription in m y e l o i d cells because of ongoing cell division. Therefore, translocation of a growth factor gene or protooncogene into the region of the histone genes could result in its activation or overexpression. This w o u l d be analogous to the overexpression of the c-myc protooncogene w h e n it is
t(2;7)(p13;q36)
203
translocated into the region of the i m m u n o g l o b u l i n genes in the t(8;14) associated with BL. In summary, we report an interesting translocation, t(2;7)(p13;q36), in a case of ANLL evolving from a long-standing MDS. A possible m e c h a n i s m for the leukemic transformation in this case w o u l d be activation of the TGFA gene or the c-rel oncogene consequent to the reciprocal translocation between ch r o m o so m es 2 and 7, perhaps due to their translocation adjacent to the histone genes on c h r o m o s o m e 7, w h i c h may be expected to be activated in m y el o i d cells. This w o u l d be analogous to c - m y c activation by translocation adjacent to the transcriptionally active Ig gene in B-cells in BL with t(8;14). It w o u l d be of value to examine the expression of the protooncogene c-rel, TGFA, and histone genes in these leukemic cells. Supported in part by Grant CA-41285. The authors acknowledge Joan Schumer for her expert technical assistance, Kathy Carr for help with the illustration, and Diane Smith for secretarial assistance.
REFERENCES 1. Sandberg AA (1980): The Chromosomes in Human Cancer and Leukemia. Elsevier North° Holland, NY, pp. 262-347. 2. Yunis JJ (1986): Chromosomal rearrangements, genes, and fragile sites in cancer: Clinical and biological implications. In: Important Advances in Oncology--1986, V Devita, S Hellman, S Rosenberg, eds. JB Lippincott, Philadelphia, pp. 93-128. 3. Fourth International Workshop on Chromosomes in Leukemia, 1982 (1984): Abnormalities of chromosome 7 resulting in monosomy 7 or in deletion of the long arm (7q-): Review of translocations, breakpoints, and associated abnormalities. Cancer Genet Cytogenet 11:300-303. 4. Second MIC Cooperative Study Group (1986): Morphologic, immunologic and cytogenetic (MIC) working classification of acute myeloid leukemias. Cancer Genet Cytogenet 30:1-15 (1988). 5. Third MIC Cooperative Study Group (1988): Morphologic, immunologic, and cytogenetic (MIC) working classification of the primary myelodysplastic syndrome and therapy-related myelodysplasias and leukemias. Cancer Genet Cytogenet 32:1-10 (1988). 6. Mitelman F (1985): Catalog of Chromosome Aberrations in Cancer. AA Sandberg Ed, Alan R. Liss, NY, pp. 1-707. 7. Brissenden JE, Derynck R, Francke U (1985): Type alpha transforming growth factor gene maps to human chromosome 2 close to the breakpoint of the t(2;8) variant translocation in Burkitt lymphoma. Cancer Res 45:5593. 8. Tricoli JV, Nakai H, Byers MG, Rail LB, Bell GI, Shows TB (1985): Assignment of the gene coding for human TGF alpha to chromosome 2p13. Eighth International Workshop on Human Gene Mapping. Cytogenet Cell Genet 40:762. 9. Brownell E, Kozak CA, Fowle JR III, Modi WS, Rice NR, O'Brien SJ (1986): Comparative genetic mapping of cellular rel sequences in man, mouse and domestic cat. Am J Hum Genet 39:194-202. 10. Robson EB, Meera Khan P (1982): Report of the committee on the genetic constitution of chromosomes 7, 8, and 9 (HGM6). Cytogenet Cell Genet 32:144-152. 11. Yunis JJ (1976): High resolution of human chromosomes. Science 191:1268-1270. 12. Yunis JJ (1981): New chromosome techniques in the study of human neoplasia. Hum Pathol 12:540-549. 13. de la Maza M, Sanchez O (1976): Simultaneous G and C banding of human chromosomes. J Med Genet 13:235-236. 14. ISCN (1985): An International System for Human Cytogenetic Nomenclature, Harnden DG, Klinger HP (eds.), published in collaboration with Cytogenet Cell Genet (Karger, Basel, 1985); also in Birth Defects: Original Article Series, Vol. 21, No. 1 (March of Dimes Birth Defects Foundation, NY, 1985).
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15. Sandberg AA (1984): Chromosomal alterations associated with neoplasia. Transplant Proc 16:366-369. 16. Sandberg AA (1986): The chromosomes in h u m a n leukemia. Semin Hematol 23:201-217. 17. Koeffler HP (1986): Myelodysplastic syndromes (Preleukemia). Semin Hematol 23:284299. 18. Klein G (1983): Specific chromosomal translocations and the genesis of B-cell-derived tumors in mice and man. Cell 32:311-315. 19. Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G (1984): Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36:93-99. 20. Sonnier JA, Buchanan GR, Howard-Peebles PN, Rutledge J, Smith RG (1983): Chromosomal translocation involving the immunoglobulin kappa-chain and heavy-chain loci in a child with chronic lymphocytic leukemia. N Engl J Med 309:590-594. 21. Fell HP, Smith RG, Tucker PW (1986): Molecular analysis of the t(2;14) translocation of childhood chronic lymphocytic leukemia. Science 232:491-494. 22. Yunis JJ, Soreng AL (1984): Constitutive fragile sites and cancer. Science 226:1199-1204. 23. Sandberg AA, Morgan R, Berger C, Kaiser-McCaw Hecht B, Hecht F (1984): Chromosome analysis in hematologic disorders. The leukemia. Am J Med 76:971-982. 24. Ferti A, Panani A, Arapatis G, Raptis S (1984): Cytogenetic study in multiple myeloma. Cancer Genet Cytogenet 12:247-253. 25. Geisler C, Philip P, Plesner T, Anderson P, Zeuthen J, Guldhammer B, Hansen MM (1986): Simultaneous presence of translocations t(14;18) and t(2;8) in a case of chronic lymphocytic leukemia. Cancer Genet Cytogenet 22:35-44. 26. Collins MKL, Goodfellow PN, Dunne MJ, Spurr NK, Solomon E, Owen MJ (1984): A human T-cell antigen receptor beta chain gene maps to chromosome 7. EMBO J 3:2347. 27. Morton CC, Duby AD, Eddy RL, Shows TB, Seidman JG (1985): Genes for beta chain of h u m a n T-cell antigen receptor map to regions of chromosomal rearrangement in T cells. Science 228:582-585. 28. Le Beau MM, Diaz MD, Rowley SD, Mak TW (1985): Chromosomal localization of the h u m a n T cell receptor beta chain genes. Cell 41:335. 29. Brito-Babapulle V, Matutes E, Parreira L, Catovsky D (1986): Abnormalities of chromosome 7q and Tac expression in T-cell leukemias. Blood 67:516. 30. Raimondi SC, Pui C-H, Behm FG, Williams DL (1987): 7q32-q36 translocations in childhood T cell leukemia: Cytogenetic evidence of involvement of the T cell receptor 13-chain gene. Blood 69:131-134. 31. Calabretta B, Venturelli D, Kaczmarek L, Narni F, Talpaz M, Anderson B, Beran M, Baserga R (1986): Altered expression of Gl-specific genes in h u m a n malignant myeloid cells. Proc Natl Acad Sci USA 83:1495-1498. A d d e n d u m : The patient's leukemia relapsed in May 1988, with 35% blasts in the bone marrow. Cytogenetic study of the bone marrow showed 19 metaphases with t(2;7)(p13;q36) and three normal metaphases (46,XY). A second bone marrow aspirate in late May contained 72% blasts. Cytogenetic Study at this time showed 17 metaphases with t(2;7)(p13;q36) and no normal metaphases. The patient's leukemia has not responded to reinduction therapy with highdose cytosine arabinoside.
A case of acute nonlymphocytic leukemia with a new translocation, t(2;7)(p13;q36), as the sole karyotypic abnormality is reported. The patient's leukemia evolved from a cytogenetically normal myelodysplastic syndrome of 4 years' duration. Following treatment the patient entered complete remission with loss of the cytogenetically abnormal clone. Subsequent bone marrow analyses showed recurrence of the myelodysplastic syndrome with a normal karyotype. Although both chromosomes 2 and 7 are known to be involved in nonrandom karyotypic changes in human cancer and leukemia, t(2;7)(p13;q36) has not been reported previously.
ABSTRACT:
INTRODUCTION Cytogenetic analyses of h u m a n leukemias performed using improved culture and b a n d i n g techniques indicate an increase from the previously reported 50% abnormalities in acute n o n l y m p h o c y t i c leukemia (ANLL) [1]. Many laboratories are currently finding that 70%-80% of patients have a cytogenetically abnormal clone, and Yunis et al. [2] have observed that approximately 90% of their cases have an abnormal karyotype. Several hematologic conditions, i n c l u d i n g preleukemias, are associated with abnormalities of chromosome 7 [3-5]. Reports of the specific involvement of chromosome 2 in aberrations are less c o m m o n [6]. We report herein an elderly patient with a translocation between chromosomes 2 and 7 with breaks at band 2p13, the region to which the transforming growth factor alpha (TGFA) [7, 8] and the c-re/ protooncogene [9] have been mapped, and band 7q36 to which the histone genes [10] have been localized. This finding is of great interest because molecular studies of cancer-associated chromosomal abnormalities indicate that such rearrangements may initiate transformation by activating cellular oncogenes and growth factor genes that lie w i t h i n or near the chromosomal breakpoints. The presence of these genes at the breakpoint in the t(2;7)(p13;q36) suggests m e c h a n i s m s by which the leukemic phenotype may have supervened in our patient. From the Departmentsof Geneticsand Endocrinology(C. S., F. S.) and HematologicOncology(M. R. B., H. D. P.), Roswell Park Memorial Institute, Buffalo. NY and the Genetics Center, Southwest Biomedical Research Institute, Scottsdale, AZ (A. A. S.). Address requests for reprints to Dr. Avery A. Sandberg, The Genetics Center, Southwest Biomedical Research Institute, 6401 E. Thomas Rd., Scottsdale, AZ 85251. Received April 11, 1988; accepted June 13, 1988.
199 c'. 1988 ElsevierScience PublishingCo.. Inc. 655 Avenueof the Americas,New York, NY 10010
Cancer Genet Cytogenel35:199 204 (1988) 0165-4608/88/$03.50
200
C. Sreekantaiah et al.
CASE REPORT
The patient is a 73-year-old white male, a retired politician without significant past medical or occupational history. He presented in 1983 at age 68 with a hemoglobin (Hb) of 10.7 g/dl, white blood cell count (WBC) 4600/mm 3 with 28% granulocytes, and platelet count 233,000/mm 3. Mean corpuscular volume was 104 fl, and reticulocyte count was 1%. Iron, B12, and folate levels were normal. The bone marrow was normocellular with a myeloid:erythroid ratio of 4:1, with 6% blasts and 9% promyelocytes. A diagnosis of myelodysplastic syndrome (MDS) was made. The patient's blood counts remained stable, and he required no therapeutic intervention until August 1987 when he presented with Hb 7.1 g/dl and WBC 16,O00/mm 3, with 20% blasts and 26% immature monocytes. Platelet count was 916,000/ram 3. Bone marrow cellularity was 50% with 47% blasts. Megaloblastic erythroid precursors were present, as were Pelger-Huet cells and dysplastic megakaryocytes. Auer rods were seen in the bone marrow blasts. Fifty-five percent of the bone marrow blasts stained with peroxidase, 55% with Sudan black, and 70% with nonspecific esterase. A diagnosis of acute myelogenous leukemia, FAB type M4, was made. The patient was treated with high-dose cytosine arabinoside and daunorubicin (September 1987) and achieved complete remission. In October 1987, the patient's Hb was 9.7 g/dl, WBC 5300/ram 3 with 31% granulocytes, and platelet count 435,000/mm 3. His bone marrow was hypocellular, with normal erythroid and myeloid precursors and megakaryocytes. He received one course of consolidation therapy with high-dose cytosine arabinoside and daunorubicin. Further consolidation therapy was not administered because of cardiac problems. He has not had a recurrence of the leukemia, but has developed recurrent anemia, necessitating red blood cell transfusions. Bone marrow analyses performed in December 1987 and January 1988 showed erythroid hypoplasia with megatobtastic changes, suggestive of recurrence of the MDS. CYTOGENETIC ANALYSIS Chromosomal studies were performed on short-term (48 hour) cultures of bone marrow samples using a high-resolution banding technique [11] with methotrexate synchronization. Slides prepared by an air-drying method were G banded with Wright stain [12] and/or stained using a combined G- and C-banding technique [13]. Karyotypes were expressed according to standard nomenclature [14]. The results of serial cytogenetic examinations of the bone marrow cells are shown in Table 1. The initial karyotypic analysis of the patient's bone marrow, at the time of diagnosis of MDS in 1983, revealed a normal karyotype. Chromosomal analysis done in 1987, when he was diagnosed as having ANLL-M4 showed a reciprocal translocation between chromosomes 2 and 7, t(2;7)(p13;q36), as the sole abnormality in all the cells analyzed (Fig. 1). Another pretreatment sample obtained 10 days later showed the same abnormality. One metaphase with a normal karyotype was seen. Subsequent analyses of bone marrow samples in remission and with recurrence of MDS all revealed normal karyotypes with total disappearance of the abnormal clone. DISCUSSION
Banding studies during the past decade have established correlations between specific chromosomal abnormalities and specific cancers and leukemias [2, 15]. In ANLL, morphologic subtypes have been shown to be associated with specific translocations and other changes [4, 16]. The MDS conditions, which progress to leuke-
(2;7)(p13:q36)
Table 1
201
Cytogenetic and clinical data on the bone marrow samples of the patient
Date of sampling
Diagnosis
Number of cells analyzed
Karyotype (Number of cells) 46,XY (27) 45,XY, random loss (3) 46,XY,t(2;7)(p13;q36) (15) 45,X,- Y,t(2;7)(p13;q36) (1) 46,XY,t(2;7)(p13;q36) (17) 46,XY (1) 46,XY (20)
7/21/83
MDS
30
9/1/87
AML pretreatment
16
9/11/87
AML pretreatment
18
10/23/87
AML remission, preconsolidation #1 Postconsolidation #1; recurrent MDS? MDS
20
12/21/87 1/19/88
22
46,XY (20) 45,XY, random loss (2)
20
46,XY (20)
mia in 10%-60% of cases [17], are also characterized by specific chromosomal defects, w h i c h generally resemble those seen in ANLL [5]. From molecular studies of specific translocations, it is apparent that the sites of consistent rearrangements specify c h r o m o s o m e segments that contain genes important in malignant transformation, specifically protooncogenes and other genetic loci for growth factors and growth factor receptors. Examples include the c - m y c translocations in Burkitt lymp h o m a {BL) [18] and the P h i l a d e l p h i a (Ph) translocation in chronic myeloblastic leukemia [19]. Our patient, who had no history of toxic exposure, was diagnosed as having MDS in 1983, at w h i c h time cytogenetic analysis revealed a normal karyotype. He presented in August 1987 with acute myeloblastic leukemia (AML), and this time karyotypic analysis revealed a t(2;7)(p13;q36). This translocation has not been reported previously. The breakpoints involved, 2p13 and 7q36, suggest m e c h a n i s m s whereby leukemic transformation may have occurred in this case. Abnormalities of c h r o m o s o m e 2 are seen infrequently in cancer i n c l u d i n g leukemia. The specific changes involving chromosome 2 include the variant t(2;8) in BL (eight cases described in [6]) and B-type acute l y m p h o c y t i c leukemia (B-ALL) (four cases described in [6]), and t(2;14) in chronic l y m p h o c y t i c leukemia (CLL) [20, 21]. The translocation breakpoint on chromosome 2, 2p13, in our case is of interest for a n u m b e r of reasons. Band 2p13 is a fragile site; fragile sites are k n o w n to have a significant correlation with the location of oncogenes and specific cancer c h r o m o s o m e breakpoints [22]. This band might thus exhibit a p r o p e n s i t y to be involved in cancer-associated translocations. It is interesting that 2p13 is near the region of breaks (2p11-p13) involved in various translocations; the t(2;8) in BL and p r e - B - and B-ALL [6], t(2;14) in B-CLL [20, 21], t(2;5) in a case of AML [23], and t(2;8) in m u l t i p l e m y e l o m a [24] and CLL [25]. Band 2p13 is the locus of the gene for the transforming growth factor alpha (TGFA) [7, 8]. The TGFA has been i m p l i c a t e d in tumor proliferation and cell transformation, perhaps by an autocrine feedback mechanism. Thus, a break in this region suggests that TGFA might have contributed to the leukemic progression in this case. The oncogene c-rel also has been localized to 2cen-2p13 [9], and a break in this
202
c. Sreekantaiah et al.
1
2
3
4
5
l 6
7
13
14
mp
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4~
20
21
19
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8
9
15
10
16
11
17
12
18
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22
X Y
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Figure 1 G-banded karyotype of the patient at the time of diagnosis of AML showing the t(2;7)(p13;q36) abnormality. region might result in its abnormal expression or overexpression, resulting in leukemic transformation. A n u m b e r of hematologic malignancies are frequently associated with aberrations of c h r o m o s o m e 7 [3-5] and our findings are consistent with this involvement. Secondary ANLL in particular is characterized by n o n r a n d o m changes either as - 7 or 7 q - . These patients generally have a history of exposure to toxic substances or radiation, including treatment for previous malignancy. Our patient was different in that he had no history of toxic exposure and the chromosomal aberration did not involve the loss of any part of chromosome 7, but instead was a translocation at the terminal band on the long arm, 7q36. The genes localized to this region are the Tcell receptor f3-chain gene [26-28], w h i c h has been postulated to be activated by translocations involving 7q32-36 in c h i l d h o o d T-ALL [29, 30] and the genes for histones [9]. The histone H3 gene has been demonstrated to be transcribed in normal as well as leukemic bone marrow [31]. All of the histone genes m a y in fact be expected to be undergoing transcription in m y e l o i d cells because of ongoing cell division. Therefore, translocation of a growth factor gene or protooncogene into the region of the histone genes could result in its activation or overexpression. This w o u l d be analogous to the overexpression of the c-myc protooncogene w h e n it is
t(2;7)(p13;q36)
203
translocated into the region of the i m m u n o g l o b u l i n genes in the t(8;14) associated with BL. In summary, we report an interesting translocation, t(2;7)(p13;q36), in a case of ANLL evolving from a long-standing MDS. A possible m e c h a n i s m for the leukemic transformation in this case w o u l d be activation of the TGFA gene or the c-rel oncogene consequent to the reciprocal translocation between ch r o m o so m es 2 and 7, perhaps due to their translocation adjacent to the histone genes on c h r o m o s o m e 7, w h i c h may be expected to be activated in m y el o i d cells. This w o u l d be analogous to c - m y c activation by translocation adjacent to the transcriptionally active Ig gene in B-cells in BL with t(8;14). It w o u l d be of value to examine the expression of the protooncogene c-rel, TGFA, and histone genes in these leukemic cells. Supported in part by Grant CA-41285. The authors acknowledge Joan Schumer for her expert technical assistance, Kathy Carr for help with the illustration, and Diane Smith for secretarial assistance.
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