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A Translocation Breakpoint at Chromosome Band 12q13 Associated with B-Cell Chronic Lymphocytic Leukemia
A Translocation Breakpoint at Chromosome Band 12q13 Associated with B-Cell Chronic Lymphocytic Leukemia A. Dean Stock and Thomas R. Dennis
ABSTRACT: Low-grade B-cell lymphoproliferative disorders are frequently associated with an extra copy of chromosome 12. This well-documented acquired anomaly is one of the most specific numerical chromosome alterations to occur in human hematological malignancies. We have cytogenetically characterized bone marrow and peripheral blood cells from a patient with B-cell chronic lymphocytic leukemia (CLL) having a unique acquired translocation involving chromosomes 6 and 12, t(6;12)(p21.3;q13), which implicates band 12q13 as the site of the gene(s) important in this lymphoproliferative B-cell disorder. Aneuploidy, in the form of trisomy of chromosome 12, is not a requirement for neoplastic transformation in B-cell CLL, but gene rearrangement (present case) or nondisjunctional acquisition of additional copies of defective genes on chromosome 12 at band q13 may be involved in the genesis or progression of this disorder. © Elsevier Science Inc., 1999. All rights reserved.
INRODUCTION Acquired clonal chromosomal aberrations characterize the majority of cases of malignant hematological disease [1]. Usually these changes involve structural rearrangements in specific chromosomes, and alter the function of genes responsible for the genesis of malignancy through the genetic mechanisms of gene activation and gene fusion [2]. A high frequency of trisomy 12 has been associated with certain low-grade B-cell lymphoproliferative disorders, specifically B-cell chronic lymphocytic leukemia (B-CLL) and diffuse B-small cell lymphocytic lymphoma [3–9]. A mechanism of gene dosage has been suggested to explain malignancies characterized by trisomy of specific chromosomes [10]. Cytogenetic studies performed on a bone marrow specimen obtained during clinical evaluation of a 63-year-old male patient with chronic lymphocytic leukemia revealed a reciprocal translocation between chromosome 6 and chromosome 12 as the sole abnormality associated with a diagnosis of CLL. Review of the peripheral blood smear revealed abundant lymphocytosis. The results of immunologic studies done on cells in suspension indicated a monoclonal B-cell population characterized by IgM heavy chain and lambda light chain (IgM lambda). Clinically, the patient
From the Department of Pathology, University of Nevada School of Medicine, Reno, Nevada, USA. Address reprint requests to: Dr. A. D. Stock, Director, Molecular Cytogenetics Laboratory, Department of Pathology, University of Nevada School of Medicine, 704 Mill Street, Reno, NV 89502. Received August 12, 1998; accepted October 31, 1998. Cancer Genet Cytogenet 111:166–168 (1999) Elsevier Science Inc., 1999. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
was considered to have common type CLL, well differentiated stage IV with cervical lymph node involvement. MATERIALS AND METHODS Cytogenetic studies were performed on 24- and 48-hour unstimulated and 72-hour methotrexate-synchronized bone marrow cultures in addition to peripheral blood lymphocyte cultures. All cultures were grown in RPMI-1640 medium supplemented with 20% fetal bovine serum (FBS). Cultures were harvested, and banded chromosome preparations were made using the techniques employed in our laboratory for hematologic malignancies [11]. RESULTS Twenty well-spread G-banded metaphase cells were analyzed and photographed for each specimen. The level of resolution included cells up to 800 bands. No abnormal metaphases were noted in peripheral blood. The karyotype in all 20 cells from bone marrow was 46,XY,t(6;12) (p21.3;q13). Selected triplets of G-banded chromosomes 6 and 12 were compared to the ISCN standard ideogram and the breakpoints shown by arrows (Fig. 1). DISCUSSION The results of this study confirm and refine previous reports implicating genes on the long arm of chromosome 12 in B-cell CLL. Several cases have been reported with either entire or partial trisomy of the long arm of chromo-
0165-4608/99/$–see front matter PII S0165-4608(98)00247-7
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B-CLL with Translocation 12q13
Figure 1 Partial karyotypes demonstrating the two chromosomes derived from the translocation (6;12)(p21.3;q13). The triplet on the left has the derived chromosomes arranged to match the normal 6. The triplet on the right has different copies of the same derived chromosomes inverted to match the normal 12. Arrows indicate the breakpoints.
some 12 [12–18]. Each of these cases was trisomic for at least a portion of 12q. Notably, each instance of partial long-arm trisomy included a breakpoint at 12q13. In our case, however, the only abnormality observed was a translocation (6;12)(p21.3;q13) resulting in a break in 12q13 but no triplication of any region of 12q. This fortuitous observation suggests that a specific gene at 12q13 is critical in B-cell CLL and that rearrangement of this gene is sufficient to cause the same effect produced by the more commonly occurring trisomy 12. Several genes have been identified in band 12q13 which have functions related to cell growth including an oncogene: INT-1, GLI, CHOP, SP1, SAS, and MDM2 [19–23]. With the exception of MDM2, these genes have not been implicated in CLL [19, 24]. MDM2 has recently been reported to be overexpressed in some cases [25], or to be rearranged, but not amplified or overexpressed in other cases [26]. The occurrence of a specific translocation with no resulting triplication strongly suggests that band 12q13 carries a gene which, when altered, contributes to the development of B-CLL. It is possible that in this case, a gene carried on chromosome 6p contributed to increased activity of a specific gene on chromosome 12q, thus duplicating the effects of having an additional copy of the gene involved. However, we believe that it is unlikely that simple aneuploidy in the form of trisomy 12 is responsible for the genesis of B-CLL. Rather, the presence of an additional copy of chromosome 12 with an altered gene at 12q13 contributes to the development of B-cell CLL. Gene dosage in the form of trisomy for specific chromosomes has been suggested as a mechanism contributing to malignancy [10, 27]. However, the occurrence of individuals with mosaic trisomy 8 or complete trisomy 21 without malignancy, and this case of CLL without trisomy 12, suggests that trisomy alone is unlikely to be the initiating
cause of malignancy. The recent identification of ALL1 gene self-fusion in AML patients with trisomy 11, representing the first identification of a specific gene defect associated with trisomy in leukemia, suggests that the concept of gene dosage must be reevaluated [28]. More likely, an initiating event is a rearrangement, activation, or loss of a gene which starts a cascade of events leading to selection for greater malignancy. This selection may take the form of trisomy for specific chromosomes, which, as has been suggested for the ALL1 gene product, may involve the formation of abnormal protein complexes through a dominant negative mechanism [29]. In CLL, trisomy 12 is associated with atypical lymphocyte morphology and a more aggressive disease progression with an unfavorable prognosis [7, 18]. It may well be that duplication of a previously rearranged gene at 12q13 is responsible for these attributes in a manner similar to duplication of a rearranged gene for the BCR-ABL fusion protein upon acquisition of an additional Philadelphia chromosome during disease progression in chronic myelogenous leukemia. We thank Drs. Stephen Forman and George Somlo, Department of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, for providing the bone marrow specimen and clinical diagnosis. The laboratory portion of this study was accomplished at the Cytogenetics Laboratory, Department of Anatomic Pathology, City of Hope National Medical Center, Duarte, California.
REFERENCES 1. Yunis JJ (1983): The chromosomal basis of human neoplasia. Science 221:227–236. 2. Croce CM (1987): Role of chromosome translocations in human neoplasia. Cell 49:155–156. 3. Gahrton G, Robèrt K-H, Friberg K, Zech L, Bird AG (1980): Nonrandom chromosomal aberrations in chronic lymphocytic leukemia revealed by polyclonal B-cell-mitogen stimulation. Blood 56:640–647. 4. Knuutila S, Elonen E, Teerenhovi L, Rossi L, Leskinen R, Bloomfield CD, de la Chapelle A (1986): Trisomy 12 in B cells of patients with B-cell chronic lymphocytic leukemia. N Engl J Med 314:865–869. 5. Juliusson G, Gahrton G (1990): Chromosome aberrations in B-cell chronic lymphocytic leukemia: Pathogenetic and clinical implications. Cancer Genet Cytogenet 45:143–160. 6. Anastasi J, Le Beau MM, Vardiman JW, Fernald AA, Larson RA, Rowley JD (1992): Detection of trisomy 12 in chronic lymphocytic leukemia by fluorescence in situ hybridization to interphase cells: a simple and sensitive method. Blood 79:1796–1801. 7. Matutes E, Oscier D, Garcia-Marco J, Ellis J, Copplestone A, Gillingham R, Hamblin T, Lens D, Swansbury GJ, Catovsky D (1996): Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol 92:382–388. 8. Acar H, Connor MJ (1998): Detection of trisomy 12 and centromeric alterations in CLL by interphase- and metaphaseFISH. Cancer Genet Cytogenet 100:148–151. 9. Stilgenbauer S, Döhner K, Bentz M, Lichter P, Döhner H (1998): Molecular cytogenetic analysis of B-cell lymphocytic leukemia. Ann Hematol 76:101–110.
168 10. Crossen PE, Horn HL (1987): Origin of trisomy 12 in B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 28: 185–186. 11. Goodman BK, Xu W-T, Nottoli V, Rundall-Jackson T, Stock AD (1985): A simple technique for bone marrow preparations with modified hypotonic treatment. Karyogram 11:95–96. 12. Mecucci C, Delannoy A, Van Den Berghe H (1988): The origin of trisomy 12 in B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 36:203–204. 13. McManus AP, Bailie KEM, Jess H, Desai ZR (1994): A derivative chromosome 14 resulting in partial trisomy of chromosome 12 in B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 76:159–160. 14. Dierlamm J, Wlodarska I, Michaux L, Vermeesch JR, Meeus P, Stul M, Criel A, Verhoef G, Thomas J, Delannoy A, Louwagie A, Cassiman J-J, Mecucci C, Hagemeijer A, Van den Berghe H (1997): FISH identifies different types of duplications with 12q13–15 as the commonly involved segment in B-cell lymphoproliferative malignancies characterized by partial trisomy 12. Genes Chromosom Cancer 20:155–166. 15. Gahrton G, Robert K-H, Friberg K, Juliusson G, Biberfeld P, Zech L (1982): Cytogenetic mapping of the duplicated segment of chromosome 12 in lymphoproliferative disorders. Nature 297:513–514. 16. Juliusson G, Friberg K, Gahrton G (1988): Consistency of chromosomal aberrations in chronic B-lymphocytic leukemia. A longitudinal cytogenetic study of 41 patients. Cancer 62:500–506. 17. Döhner H, Pohl S, Bulgay-Mörschel M, Stilgenbaur S, Bentz M, Lichter P (1993): Trisomy 12 in chronic lymphoid leukemias—a metaphase and interphase cytogenetic analysis. Leukemia 7:516–520. 18. Merup M, Juliusson G, Wu X, Jansson M, Stellan B, Rasool O, Röijer E, Stenman G, Gahrton G, Einhorn S (1997): Amplification of multiple regions of chromosome 12, including 12q13–15, in chronic lymphocytic leukemia. Eur J Haematol 58:174–180.
A. D. Stock and T. R. Dennis 19. Crossen PE (1989): Cytogenetic and molecular changes in chronic B-cell leukemia. Cancer Genet Cytogenet 43:143–150. 20. Åman P, Ron D, Mandahl N, Fioretos T, Heim S, Arheden K, Willén H, Rydholm A, Mitelman F (1992): Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11). Genes Chromosom Cancer 5:278–285. 21. Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B (1992): Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 358:80–83. 22. Meltzer PS, Jankowski SA, Dal Cin P, Sandberg AA, Paz IB, Coccia MA (1991): Identification and cloning of a novel amplified DNA sequence in human malignant fibrous histiocytoma derived from a region of chromosome 12 frequently rearranged in soft tissue tumors. Cell Growth Differ 2:495–501. 23. Gaynor RB, Shieh B-H, Klisak I, Sparkes RS, Lusis AJ (1993): Localization of the transcription factor SP1 gene to human chromosome 12q12→q13.2. Cytogenet Cell Genet 64:210–212. 24. Craig I, Gemmill R, Kucherlapati R (1992): Report of the first international workshop on human chromosome 12 mapping. Cytogenet Cell Genet 61:243–262. 25. Watanabe T, Hotta T, Ichikawa A, Kinoshita T, Nagai H, Uchida T, Murate T, Saito H (1994): The MDM2 oncogene overexpression in chronic lymphocytic leukemia and lowgrade lymphoma of B-cell origin. Blood 84:3158–3165. 26. Huang YQ, Raphael B, Buchbinder A, Li JJ, Zhang WG, Friedman-Kien AE (1994): Rearrangement and expression of MDM2 oncogene in chronic lymphocytic leukemia. Am J Hematol 47:139–141. 27. Klein G (1981): The role of gene dosage and genetic transpositions in carcinogenesis. Nature 294:313–318. 28. Caligiuri MA, Schichman SA, Strout MP, Mrózek K, Baer MR, Frankel SR, Barcos M, Herzig GP, Croce CM, Bloomfield CD (1994): Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations. Cancer Res 54:370–373. 29. Schichman SA, Canaani E, Croce CM (1995): Self-fusion of the ALL1 gene: a new genetic mechanism for acute leukemia. JAMA 273:571–576.
ABSTRACT: Low-grade B-cell lymphoproliferative disorders are frequently associated with an extra copy of chromosome 12. This well-documented acquired anomaly is one of the most specific numerical chromosome alterations to occur in human hematological malignancies. We have cytogenetically characterized bone marrow and peripheral blood cells from a patient with B-cell chronic lymphocytic leukemia (CLL) having a unique acquired translocation involving chromosomes 6 and 12, t(6;12)(p21.3;q13), which implicates band 12q13 as the site of the gene(s) important in this lymphoproliferative B-cell disorder. Aneuploidy, in the form of trisomy of chromosome 12, is not a requirement for neoplastic transformation in B-cell CLL, but gene rearrangement (present case) or nondisjunctional acquisition of additional copies of defective genes on chromosome 12 at band q13 may be involved in the genesis or progression of this disorder. © Elsevier Science Inc., 1999. All rights reserved.
INRODUCTION Acquired clonal chromosomal aberrations characterize the majority of cases of malignant hematological disease [1]. Usually these changes involve structural rearrangements in specific chromosomes, and alter the function of genes responsible for the genesis of malignancy through the genetic mechanisms of gene activation and gene fusion [2]. A high frequency of trisomy 12 has been associated with certain low-grade B-cell lymphoproliferative disorders, specifically B-cell chronic lymphocytic leukemia (B-CLL) and diffuse B-small cell lymphocytic lymphoma [3–9]. A mechanism of gene dosage has been suggested to explain malignancies characterized by trisomy of specific chromosomes [10]. Cytogenetic studies performed on a bone marrow specimen obtained during clinical evaluation of a 63-year-old male patient with chronic lymphocytic leukemia revealed a reciprocal translocation between chromosome 6 and chromosome 12 as the sole abnormality associated with a diagnosis of CLL. Review of the peripheral blood smear revealed abundant lymphocytosis. The results of immunologic studies done on cells in suspension indicated a monoclonal B-cell population characterized by IgM heavy chain and lambda light chain (IgM lambda). Clinically, the patient
From the Department of Pathology, University of Nevada School of Medicine, Reno, Nevada, USA. Address reprint requests to: Dr. A. D. Stock, Director, Molecular Cytogenetics Laboratory, Department of Pathology, University of Nevada School of Medicine, 704 Mill Street, Reno, NV 89502. Received August 12, 1998; accepted October 31, 1998. Cancer Genet Cytogenet 111:166–168 (1999) Elsevier Science Inc., 1999. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
was considered to have common type CLL, well differentiated stage IV with cervical lymph node involvement. MATERIALS AND METHODS Cytogenetic studies were performed on 24- and 48-hour unstimulated and 72-hour methotrexate-synchronized bone marrow cultures in addition to peripheral blood lymphocyte cultures. All cultures were grown in RPMI-1640 medium supplemented with 20% fetal bovine serum (FBS). Cultures were harvested, and banded chromosome preparations were made using the techniques employed in our laboratory for hematologic malignancies [11]. RESULTS Twenty well-spread G-banded metaphase cells were analyzed and photographed for each specimen. The level of resolution included cells up to 800 bands. No abnormal metaphases were noted in peripheral blood. The karyotype in all 20 cells from bone marrow was 46,XY,t(6;12) (p21.3;q13). Selected triplets of G-banded chromosomes 6 and 12 were compared to the ISCN standard ideogram and the breakpoints shown by arrows (Fig. 1). DISCUSSION The results of this study confirm and refine previous reports implicating genes on the long arm of chromosome 12 in B-cell CLL. Several cases have been reported with either entire or partial trisomy of the long arm of chromo-
0165-4608/99/$–see front matter PII S0165-4608(98)00247-7
167
B-CLL with Translocation 12q13
Figure 1 Partial karyotypes demonstrating the two chromosomes derived from the translocation (6;12)(p21.3;q13). The triplet on the left has the derived chromosomes arranged to match the normal 6. The triplet on the right has different copies of the same derived chromosomes inverted to match the normal 12. Arrows indicate the breakpoints.
some 12 [12–18]. Each of these cases was trisomic for at least a portion of 12q. Notably, each instance of partial long-arm trisomy included a breakpoint at 12q13. In our case, however, the only abnormality observed was a translocation (6;12)(p21.3;q13) resulting in a break in 12q13 but no triplication of any region of 12q. This fortuitous observation suggests that a specific gene at 12q13 is critical in B-cell CLL and that rearrangement of this gene is sufficient to cause the same effect produced by the more commonly occurring trisomy 12. Several genes have been identified in band 12q13 which have functions related to cell growth including an oncogene: INT-1, GLI, CHOP, SP1, SAS, and MDM2 [19–23]. With the exception of MDM2, these genes have not been implicated in CLL [19, 24]. MDM2 has recently been reported to be overexpressed in some cases [25], or to be rearranged, but not amplified or overexpressed in other cases [26]. The occurrence of a specific translocation with no resulting triplication strongly suggests that band 12q13 carries a gene which, when altered, contributes to the development of B-CLL. It is possible that in this case, a gene carried on chromosome 6p contributed to increased activity of a specific gene on chromosome 12q, thus duplicating the effects of having an additional copy of the gene involved. However, we believe that it is unlikely that simple aneuploidy in the form of trisomy 12 is responsible for the genesis of B-CLL. Rather, the presence of an additional copy of chromosome 12 with an altered gene at 12q13 contributes to the development of B-cell CLL. Gene dosage in the form of trisomy for specific chromosomes has been suggested as a mechanism contributing to malignancy [10, 27]. However, the occurrence of individuals with mosaic trisomy 8 or complete trisomy 21 without malignancy, and this case of CLL without trisomy 12, suggests that trisomy alone is unlikely to be the initiating
cause of malignancy. The recent identification of ALL1 gene self-fusion in AML patients with trisomy 11, representing the first identification of a specific gene defect associated with trisomy in leukemia, suggests that the concept of gene dosage must be reevaluated [28]. More likely, an initiating event is a rearrangement, activation, or loss of a gene which starts a cascade of events leading to selection for greater malignancy. This selection may take the form of trisomy for specific chromosomes, which, as has been suggested for the ALL1 gene product, may involve the formation of abnormal protein complexes through a dominant negative mechanism [29]. In CLL, trisomy 12 is associated with atypical lymphocyte morphology and a more aggressive disease progression with an unfavorable prognosis [7, 18]. It may well be that duplication of a previously rearranged gene at 12q13 is responsible for these attributes in a manner similar to duplication of a rearranged gene for the BCR-ABL fusion protein upon acquisition of an additional Philadelphia chromosome during disease progression in chronic myelogenous leukemia. We thank Drs. Stephen Forman and George Somlo, Department of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, for providing the bone marrow specimen and clinical diagnosis. The laboratory portion of this study was accomplished at the Cytogenetics Laboratory, Department of Anatomic Pathology, City of Hope National Medical Center, Duarte, California.
REFERENCES 1. Yunis JJ (1983): The chromosomal basis of human neoplasia. Science 221:227–236. 2. Croce CM (1987): Role of chromosome translocations in human neoplasia. Cell 49:155–156. 3. Gahrton G, Robèrt K-H, Friberg K, Zech L, Bird AG (1980): Nonrandom chromosomal aberrations in chronic lymphocytic leukemia revealed by polyclonal B-cell-mitogen stimulation. Blood 56:640–647. 4. Knuutila S, Elonen E, Teerenhovi L, Rossi L, Leskinen R, Bloomfield CD, de la Chapelle A (1986): Trisomy 12 in B cells of patients with B-cell chronic lymphocytic leukemia. N Engl J Med 314:865–869. 5. Juliusson G, Gahrton G (1990): Chromosome aberrations in B-cell chronic lymphocytic leukemia: Pathogenetic and clinical implications. Cancer Genet Cytogenet 45:143–160. 6. Anastasi J, Le Beau MM, Vardiman JW, Fernald AA, Larson RA, Rowley JD (1992): Detection of trisomy 12 in chronic lymphocytic leukemia by fluorescence in situ hybridization to interphase cells: a simple and sensitive method. Blood 79:1796–1801. 7. Matutes E, Oscier D, Garcia-Marco J, Ellis J, Copplestone A, Gillingham R, Hamblin T, Lens D, Swansbury GJ, Catovsky D (1996): Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol 92:382–388. 8. Acar H, Connor MJ (1998): Detection of trisomy 12 and centromeric alterations in CLL by interphase- and metaphaseFISH. Cancer Genet Cytogenet 100:148–151. 9. Stilgenbauer S, Döhner K, Bentz M, Lichter P, Döhner H (1998): Molecular cytogenetic analysis of B-cell lymphocytic leukemia. Ann Hematol 76:101–110.
168 10. Crossen PE, Horn HL (1987): Origin of trisomy 12 in B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 28: 185–186. 11. Goodman BK, Xu W-T, Nottoli V, Rundall-Jackson T, Stock AD (1985): A simple technique for bone marrow preparations with modified hypotonic treatment. Karyogram 11:95–96. 12. Mecucci C, Delannoy A, Van Den Berghe H (1988): The origin of trisomy 12 in B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 36:203–204. 13. McManus AP, Bailie KEM, Jess H, Desai ZR (1994): A derivative chromosome 14 resulting in partial trisomy of chromosome 12 in B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet 76:159–160. 14. Dierlamm J, Wlodarska I, Michaux L, Vermeesch JR, Meeus P, Stul M, Criel A, Verhoef G, Thomas J, Delannoy A, Louwagie A, Cassiman J-J, Mecucci C, Hagemeijer A, Van den Berghe H (1997): FISH identifies different types of duplications with 12q13–15 as the commonly involved segment in B-cell lymphoproliferative malignancies characterized by partial trisomy 12. Genes Chromosom Cancer 20:155–166. 15. Gahrton G, Robert K-H, Friberg K, Juliusson G, Biberfeld P, Zech L (1982): Cytogenetic mapping of the duplicated segment of chromosome 12 in lymphoproliferative disorders. Nature 297:513–514. 16. Juliusson G, Friberg K, Gahrton G (1988): Consistency of chromosomal aberrations in chronic B-lymphocytic leukemia. A longitudinal cytogenetic study of 41 patients. Cancer 62:500–506. 17. Döhner H, Pohl S, Bulgay-Mörschel M, Stilgenbaur S, Bentz M, Lichter P (1993): Trisomy 12 in chronic lymphoid leukemias—a metaphase and interphase cytogenetic analysis. Leukemia 7:516–520. 18. Merup M, Juliusson G, Wu X, Jansson M, Stellan B, Rasool O, Röijer E, Stenman G, Gahrton G, Einhorn S (1997): Amplification of multiple regions of chromosome 12, including 12q13–15, in chronic lymphocytic leukemia. Eur J Haematol 58:174–180.
A. D. Stock and T. R. Dennis 19. Crossen PE (1989): Cytogenetic and molecular changes in chronic B-cell leukemia. Cancer Genet Cytogenet 43:143–150. 20. Åman P, Ron D, Mandahl N, Fioretos T, Heim S, Arheden K, Willén H, Rydholm A, Mitelman F (1992): Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11). Genes Chromosom Cancer 5:278–285. 21. Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B (1992): Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 358:80–83. 22. Meltzer PS, Jankowski SA, Dal Cin P, Sandberg AA, Paz IB, Coccia MA (1991): Identification and cloning of a novel amplified DNA sequence in human malignant fibrous histiocytoma derived from a region of chromosome 12 frequently rearranged in soft tissue tumors. Cell Growth Differ 2:495–501. 23. Gaynor RB, Shieh B-H, Klisak I, Sparkes RS, Lusis AJ (1993): Localization of the transcription factor SP1 gene to human chromosome 12q12→q13.2. Cytogenet Cell Genet 64:210–212. 24. Craig I, Gemmill R, Kucherlapati R (1992): Report of the first international workshop on human chromosome 12 mapping. Cytogenet Cell Genet 61:243–262. 25. Watanabe T, Hotta T, Ichikawa A, Kinoshita T, Nagai H, Uchida T, Murate T, Saito H (1994): The MDM2 oncogene overexpression in chronic lymphocytic leukemia and lowgrade lymphoma of B-cell origin. Blood 84:3158–3165. 26. Huang YQ, Raphael B, Buchbinder A, Li JJ, Zhang WG, Friedman-Kien AE (1994): Rearrangement and expression of MDM2 oncogene in chronic lymphocytic leukemia. Am J Hematol 47:139–141. 27. Klein G (1981): The role of gene dosage and genetic transpositions in carcinogenesis. Nature 294:313–318. 28. Caligiuri MA, Schichman SA, Strout MP, Mrózek K, Baer MR, Frankel SR, Barcos M, Herzig GP, Croce CM, Bloomfield CD (1994): Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations. Cancer Res 54:370–373. 29. Schichman SA, Canaani E, Croce CM (1995): Self-fusion of the ALL1 gene: a new genetic mechanism for acute leukemia. JAMA 273:571–576.