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Translocation 11;14 in newly diagnosed chronic myelogenous leukemia
Translocation
11;14 in Newly Diagnosed Chronic
Myelogenous
Leukemia
Anthony Magdalinski, Helen Drwinga, Pamela Crilley, Jerzy Lasota, Isadore Brodsky, Carlo M. Croce, Peter C. Nowell, and David I. Marks
ABSTRACT: In patients with chronic myelogenous leukemia (CML), the Philadelphia chromosome may be associated with a number of other cytogenetic lesions. However, t(11;14)(q13;q32), found mainly in B-cell lymphoproliferative disorders, has not been previously reported in Ph-positive CML. We describe a patient with hematologically typical chronic phase CML in whom both cytogenetic lesions were found at diagnosis. INTRODUCTION The first malignant disease to be characterized by a consistent cytogenetic abnormality was chronic myelogenous leukemia (CML). The Philadelphia chromosome was first described by Nowell and Hungerford in 1960 as a deletion on the part of the long arm of a G-group chromosome [l]. With the advent of modern banding techniques, Rowley [2] later demonstrated the precise translocation. Although finding additional chromosomal abnormalities precedes the development of the blastic or acute phase in 70-80% of cases of chronic-phase CML, additional cytogenetic abnormalities at diagnosis in the chronic phase have not been associated with a poor outcome [3]. The t(11;14)(q13;q32) has been described in several B-cell lymphoprolferative disorders, many of these expressing rearrangements of the bcl-1 locus [4]. To our knowledge, the occurrence of these two translocations has not been described previously. We herein describe a patient with typical CML with 46,XY,t(9;22)(q34;qll), t(11;14)(q13;q32), and the molecular studies performed to further elucidate this finding. CASE HISTORY A 37-year-old white male with a history of dyspepsia presented with fatigue, low-grade fevers, chest discomfort,
From the Department of Neoplostic Diseases (A. M., H. D., P C., D. I. M.), Hahnemann University Hospital, Broad and Vine Streets, Philadelphia; Jefferson Cancer Institute [J. L., C. M. C.), Jefferson Medical CoJJene. Thomas Jefferson Universitv, Philadelphia; and Department oflPathoJogy a&iabomtory Medicine [J? C. N:), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Address reprint requests to: Dr. David I. Marks, Department of Neoplastic Diseases, Hahnemann University Hospital, Broad and Vine Streets, Philadelphia, PA 19102. Received June 20, 1994; accepted September 7, 1994.
Cancer
Genet Cytogenet
0 Elsevier 655
Avenue
Science
Inc.,
81:24-27
and diffuse arthralgias. His physical examination was normal. A cardiac stress test, EKG, CXR, and CT scan of the abdomen were normal. A biochemical profile was normal except for an elevated LDH (320 U/L). The peripheral blood counts were WBC 22,OOO/pL, Hb 15 g/dL, and platelets 2OO,OOO/pL. WBC differential included 68% polymorphonuclear cells, 7% bands, 9% lymphocytes, 1% monocytes, 5% metamyelocytes, and 10% myelocytes. The leukocyte alkaline phosphatase score was 59. A bone marrow biopsy was performed and examination showed marked granulocytic hyperplasia; the cellularity was 80-90%. A differential of the aspirate revealed neither basophils nor eosinophils. The myeloid series had normal maturation, 2% promyelocytes, and no blasts. The M:E ratio was 15:l. Erythroid and megakaryocytic morphology was normal. Three months following the diagnosis of CML, the patient was prescribed hydroxyurea to control a rising granulocytosis. Five months after the diagnosis, he underwent an allogeneic bone marrow transplant from his HLA-identical brother, with a conditioning regimen of 16 mg/kg oral busulfan and 120 mg/kg intravenous cyclophosphamide. Prophylaxis for GVHD was comprised of cyclosporine and methotrexate. A bone marrow biopsy performed on days 21 and 100 following allogeneic transplantation showed engraftment of all three cell lines. Cytogenetic analysis of the aspirated marrow on both occasions revealed a normal male karyotype, (46,XY).
CYTOGENETIC AND MOLECULAR GENETIC INVESTIGATIONS In the initial cytogenetic study (October 1993), all 15 cells had the following karyotype: 46,XY,t(9;22)(q34;qll),t(ll;l4) (q13;q32). A second examination was done 2 months later, prior to bone marrow transplant. For cytogenetic studies, 24hour cultures were exposed to colchicine for 10 minutes (10
(1995) 0165.4606/95/$9.50
1995
of the Americas,
New
York,
NY
10010
SSDI
0165-4606(94)00191-D
25
7
6
Figure1 46,XY,t(9;22)(q34;qll),t(11;14)(q13;q32)
gg/mL) and processed by standard techniques. The chromosomes were G-banded with a trypsin-Giemsa technique [5] (Fig. 1). Thirty cells were found to contain the two translocations. One cell was found to have a normal male karyotype. To rule out the possibility of a constitutional abnormality, cytogenetic studies were performed on phytohemagglutinin-stimulated peripheral blood cells using conventional techniques. All 25 G-banded cells examined contained a normal male karyotype. Reverse transcription polymerase chain reaction studies
Table 1
Probes used to investigate
Name PB pll-F pll-D
pPl-A PW
of RNA extracted from the peripheral blood revealed a b2a2 fusion molecule [6, 71, confirming the bcrlabl rearrangement. Southern blot analysis, which can demonstrate abnormalities in 0-5% of the total cell population, failed to detect rearrangements of the immunoglobulin heavy chain gene and T-cell receptor B-chain gene [8], Southern blot analysis for the bcl-1 locus, using probes specific for the major translocation cluster (MTG) and other breakpoint sites that lie approximately 20 kb from the MTG and the first exon of the PRAM gene, revealed germline configurations [8-n] (Table I).
the bcl-1 locus
Description Specific for the major translocation cluster (MTC) Genomic fragments approximately 10 and 30 kB 5’ of the MTC Specific for the first exon of PRADl gene (154 bp PCR product) Specific for the joining region of the immunoglobulin heavy chain gene
0 G, germline configuration.
Source Tsujimoto Tsujimoto,
[ll]
Result GO
unpublished
G
M. Monne, unpublished
G
Tsujimoto
G
[12]
A. Magdalinski
26
cytic leukemias 138:591-599.
DISCUSSION
The occurrence of additional Ph-positive CML at diagnosis been accepted
universally
cytogenetic abnormalities in in the chronic phase has not
as heralding
the onset of advanced
stages of CML, although a change in karyotype during the course of the disease is considered a sign of disease progression [13,14]. However, Sokal et al. have shown that at z years after diagnosis, patients with additional cytogenetic abnormalities at presentation had an annual death rate approximately 40% higher than that seen with patients without such abnormalities [El. While TO-80% of patients entering blastic crisis show cytogenetic evolution, there has not been shown to be a specific karyotypic pattern correlating with the phenotypic expression of the blast crises, other than isochromosome of the long arm of chromosome 17 [i(lip)], which is seen with the myeloid blastic phase. In a series from the M.D. Anderson Cancer Center, patients with lymphoid transformation tended to have a lower incidence of trisomy 8 and of isochromosome 17, compared with those patients who evolved into myeioid or undifferentiated blastic crises [16]. The new CML Synthesis Prognostic Staging System supports the concept of shortened survival with cytogenetic clonal evolution but does not consider additional cytogenetic abnormalities at diagnosis a poor prognostic sign [v]. In addition, there are several case reports of patients with myeloid blastic crises whose cytogenetic pattern evolved into “characteristic” patterns associated with specific FAB ANLL subtypes. In each case, the phenotypic expression of the blast crises corresponded to its ANLL subtype [18-241. The t(11;14)(ql$q32) abnormality has been reported in a number of lymphoproliferative disorders. In association with B-CLL [25], an increased frequency of patients with prolymphocytic transformation has been reported in association with a rearrangement of the bcl-1 locus [26].The t(11,14) has been reported in diffuse small- and large-cell B-cell lymphomas, as well as in the mantle zone/intermediate lymphocytic lymphomas [27]. In multiple myeloma [28], the translocation has also been noted with bcl-1 gene rearrangements [29], At present, we are unable to determine the significance of these cytogenetic findings. The patient presented in hematologically typical chronic phase CML. There is no evidence of a monoclonal lymphoid disorder in this patient, i.e., lack of a clonal population of cells by Southern blot analyses of immunoglobulin heavy gene, T-cell B-receptor gene, and bcl-1 gene rearrangements. It will require the study of additional patients with the combined chromosomal translocations to ascertain whether a clonal lymphoid population might emerge at the time of disease progression.
lymphomas.
Am J Path01
5. Seabright M (1971): A rapid technique for human chromosomes. Lancet ii:971. 6. Gillespie DH, Cuddy K, Kolbe T, Marks DI (1994): Dissolve and capture: a strategy for analyzing mRNA in blood. Nature 367:390-391. z
Thompson JD, Bmdsky I, Yunis J (1992): Molecular quantification of residual disease in chronic myelogenous leukemia after bone marrow transplantation. Blood 79:1629-1635.
8. Korsmeyer S (1987): Antigen receptor genes as molecular markers of lymphoid neoplasms. J Clin Invest 79:1291-1295. 9. Durst M, Cmce CM, Gissman L, Schwartz E, Huebner K (1987): Papillomavirus sequences integrate near cellular oncogenes in some cervical carcinomas. Pmc Nat1 Acad Sci USA 84:1070-l(n4. 10. Feinberg AP, Vogelstein B (1983): A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 132:6-13. 11. Tsujimoto Y, Yunis J, Onorato-Showe L, E&son J, Nowell PC, Cmce CM (1984): Molecular cloning of the chmmosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chmmosome translocation. Science 224:1403-1406. 12. Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (1984): Cloning of the cbmmosome breakpoint of neoplastic B cells with the t(11;14) chromosome translocation. Science 224:1097-1099. 13. Whang-Peng J, Canellos GP, Carbone PP, Tjio JH (1968): Clinical implications of cytogenetic variants in chronic myelocytic leukemia. Blood 32:755-766. 14. Krulik M, Smadja N, De Gramont A, Gonzales-Canali G, Audebert AA, Dray C, Brissaund P, Debray J (1987): Sequential karyotypic study on Ph-positive chronic myelocytic leukemia; significance of additional chromosomal abnormalities during disease evolution. Cancer 60:974-979. 15. Sokal JE, Gomez GA, Baccarani M, Tura S, Clarkson BD, Cervantes F, Rozman C, Carbonell F, Angar B, Heimpel H, Nissen N, Robertson JE (1988): Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome positive chronic granulocytic leukemia. Blood 72: 294-298. 16. Derderian PM, Kantarjian HM, Talpaz M, O’Brien S, Cork A, Estey E, Pierce S, Keating M (1993): Chronic Myelogenous Leukemia in the lymphoid blastic phase: characteristics, treatment response and prognosis. Am J Med 94:69-74. 1%
Kantarjian HM, Keating MJ, Smith TL, Talpaz M, McCredie KB (1990): Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia. Am J Med 88:1-8.
18. Heim S, Christensen BE, Fioretos T, Sorensen A-G, Pedersen NT (1992): Acute myelomonocytic leukemia with inv(16)(pl3q22) complicating Philadelphia chromosome positive chronic myeloid leukemia. Cancer Genet Cytogenet 59:35-38. 19. Mecucci C, Noens L, Aventin A, Testoni N, Van Den Berghe H (1988): Philadelphia-positive acute myelomonocytic leukemia with inversion of chromosome 16 and eosinophils. Am J Haematol 27:69-71. 20. Li Y-S, Hayhoe FGJ (1988): Phi chromosome positive acute myelomonocytic leukaemia with inverted chromosome 16. Br J Haematol 69:576.
REFERENCES Nowell PC, Hungerford DA (1960): A minute chromosome human chronic granulocytic leukemia. Science 132:1497.
and non-Hodgkin’s
et al.
in
Rowley JD (1973): A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine flourescence and Giemsa staining. Nature 243:290-293. Hild F, Fonatsch C (1990): Cytogenetic peculiarities in chronic myelogenous leukemia. Cancer Genet Cytogenet 47:197-2X7. Athan E, Foitl DR, Knowles DM (1991): bcl-1 rearrangement: frequency and clinical significance among B-cell chronic lympho-
21. Berger R, Bernheim A, Daniel M-T, Flandrin G (1983): t(15;17) in a promyelocytic form of chronic myeloid leukemia blastic crisis. Cancer Genet Cytogenet 8:149-152. 22. Hogge DE, Misawa S, Schiffer CA, Testa JR (1984): Promyelocytic blast crisis in chronic granulocytic leukemia with 15;17 translocation. Leukemia Res 8:1019-1023. 23. Lai J-L, Fenaux P, Zandecki M, Savarv T-B, Estienne M-H, louet J-P, Bauters F, Deminatti M (1987): Pr&yelocytic blast crisis of Philadelphia-positive thrombocythemia with translocations (9;22) and (15;17). Cancer Genet Cytogenet 29:311-314.
t(11;14)
Translocation
27
in CML
24. Louwagie AC, Mecucci C, Criel A, Van Hoof A, Van Den Berghe H (1987): Variant translocation t(l5q;ljp) accompanying a promyelocytic accelerated phase of Ph-positive chronic myeloid leukemia. Cancer Genet Cytogenet 28:349-352.
2%
Leroux D, Le Marc’Hadour F, Gressin R, Jacob MC, Keddari E, Monteil M, Caillot P, Jalbert P, Sotto JT (1991): Non-Hodgkin’s lymphomas with t(11;14)(q13;q32): a subset of mantle zone/ intermediate lymphocytic lymphoma? Br J Haematol77:346-353.
25. Nowell PC, Shankey TV, Finan J, Guerry D, Besa E (1981): Pmliferation, differentiation, and cytogenetics of chronic leukemia B lymphocytes cultured with mitomycin-treated normal cells. Blood 57~444-451.
28. van den Berghe H, Vermaelen K, Louwagie A, Criel A, Mecucci C, Vaerman JP (1984): High incidence of chromosomal abnormalities in IgG3 myeloma. Cancer Genet Cytogenet 11:381-387.
26. Newman R, Davey F, Kornfeld SB, Collins H, Brabyn C, Bloomfield CD, Royston I (1990): Correlation of immunophenotype and bcl-1 gene rearrangements with morphology in B cell chronic lymphocytic leukemia (abstract). Blood 76(suppl 1):304a.
29. Meeker TC, Grimaldi JC, O’Rourke R, Louie E, Juliusson G, Einhorn S (1989): An additional breakpoint region in the bcl-1 locus associated with the t(11;14)(q13;q32) translocation in Blymphocyte malignancy. Blood 74:1801-1806.
11;14 in Newly Diagnosed Chronic
Myelogenous
Leukemia
Anthony Magdalinski, Helen Drwinga, Pamela Crilley, Jerzy Lasota, Isadore Brodsky, Carlo M. Croce, Peter C. Nowell, and David I. Marks
ABSTRACT: In patients with chronic myelogenous leukemia (CML), the Philadelphia chromosome may be associated with a number of other cytogenetic lesions. However, t(11;14)(q13;q32), found mainly in B-cell lymphoproliferative disorders, has not been previously reported in Ph-positive CML. We describe a patient with hematologically typical chronic phase CML in whom both cytogenetic lesions were found at diagnosis. INTRODUCTION The first malignant disease to be characterized by a consistent cytogenetic abnormality was chronic myelogenous leukemia (CML). The Philadelphia chromosome was first described by Nowell and Hungerford in 1960 as a deletion on the part of the long arm of a G-group chromosome [l]. With the advent of modern banding techniques, Rowley [2] later demonstrated the precise translocation. Although finding additional chromosomal abnormalities precedes the development of the blastic or acute phase in 70-80% of cases of chronic-phase CML, additional cytogenetic abnormalities at diagnosis in the chronic phase have not been associated with a poor outcome [3]. The t(11;14)(q13;q32) has been described in several B-cell lymphoprolferative disorders, many of these expressing rearrangements of the bcl-1 locus [4]. To our knowledge, the occurrence of these two translocations has not been described previously. We herein describe a patient with typical CML with 46,XY,t(9;22)(q34;qll), t(11;14)(q13;q32), and the molecular studies performed to further elucidate this finding. CASE HISTORY A 37-year-old white male with a history of dyspepsia presented with fatigue, low-grade fevers, chest discomfort,
From the Department of Neoplostic Diseases (A. M., H. D., P C., D. I. M.), Hahnemann University Hospital, Broad and Vine Streets, Philadelphia; Jefferson Cancer Institute [J. L., C. M. C.), Jefferson Medical CoJJene. Thomas Jefferson Universitv, Philadelphia; and Department oflPathoJogy a&iabomtory Medicine [J? C. N:), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Address reprint requests to: Dr. David I. Marks, Department of Neoplastic Diseases, Hahnemann University Hospital, Broad and Vine Streets, Philadelphia, PA 19102. Received June 20, 1994; accepted September 7, 1994.
Cancer
Genet Cytogenet
0 Elsevier 655
Avenue
Science
Inc.,
81:24-27
and diffuse arthralgias. His physical examination was normal. A cardiac stress test, EKG, CXR, and CT scan of the abdomen were normal. A biochemical profile was normal except for an elevated LDH (320 U/L). The peripheral blood counts were WBC 22,OOO/pL, Hb 15 g/dL, and platelets 2OO,OOO/pL. WBC differential included 68% polymorphonuclear cells, 7% bands, 9% lymphocytes, 1% monocytes, 5% metamyelocytes, and 10% myelocytes. The leukocyte alkaline phosphatase score was 59. A bone marrow biopsy was performed and examination showed marked granulocytic hyperplasia; the cellularity was 80-90%. A differential of the aspirate revealed neither basophils nor eosinophils. The myeloid series had normal maturation, 2% promyelocytes, and no blasts. The M:E ratio was 15:l. Erythroid and megakaryocytic morphology was normal. Three months following the diagnosis of CML, the patient was prescribed hydroxyurea to control a rising granulocytosis. Five months after the diagnosis, he underwent an allogeneic bone marrow transplant from his HLA-identical brother, with a conditioning regimen of 16 mg/kg oral busulfan and 120 mg/kg intravenous cyclophosphamide. Prophylaxis for GVHD was comprised of cyclosporine and methotrexate. A bone marrow biopsy performed on days 21 and 100 following allogeneic transplantation showed engraftment of all three cell lines. Cytogenetic analysis of the aspirated marrow on both occasions revealed a normal male karyotype, (46,XY).
CYTOGENETIC AND MOLECULAR GENETIC INVESTIGATIONS In the initial cytogenetic study (October 1993), all 15 cells had the following karyotype: 46,XY,t(9;22)(q34;qll),t(ll;l4) (q13;q32). A second examination was done 2 months later, prior to bone marrow transplant. For cytogenetic studies, 24hour cultures were exposed to colchicine for 10 minutes (10
(1995) 0165.4606/95/$9.50
1995
of the Americas,
New
York,
NY
10010
SSDI
0165-4606(94)00191-D
25
7
6
Figure1 46,XY,t(9;22)(q34;qll),t(11;14)(q13;q32)
gg/mL) and processed by standard techniques. The chromosomes were G-banded with a trypsin-Giemsa technique [5] (Fig. 1). Thirty cells were found to contain the two translocations. One cell was found to have a normal male karyotype. To rule out the possibility of a constitutional abnormality, cytogenetic studies were performed on phytohemagglutinin-stimulated peripheral blood cells using conventional techniques. All 25 G-banded cells examined contained a normal male karyotype. Reverse transcription polymerase chain reaction studies
Table 1
Probes used to investigate
Name PB pll-F pll-D
pPl-A PW
of RNA extracted from the peripheral blood revealed a b2a2 fusion molecule [6, 71, confirming the bcrlabl rearrangement. Southern blot analysis, which can demonstrate abnormalities in 0-5% of the total cell population, failed to detect rearrangements of the immunoglobulin heavy chain gene and T-cell receptor B-chain gene [8], Southern blot analysis for the bcl-1 locus, using probes specific for the major translocation cluster (MTG) and other breakpoint sites that lie approximately 20 kb from the MTG and the first exon of the PRAM gene, revealed germline configurations [8-n] (Table I).
the bcl-1 locus
Description Specific for the major translocation cluster (MTC) Genomic fragments approximately 10 and 30 kB 5’ of the MTC Specific for the first exon of PRADl gene (154 bp PCR product) Specific for the joining region of the immunoglobulin heavy chain gene
0 G, germline configuration.
Source Tsujimoto Tsujimoto,
[ll]
Result GO
unpublished
G
M. Monne, unpublished
G
Tsujimoto
G
[12]
A. Magdalinski
26
cytic leukemias 138:591-599.
DISCUSSION
The occurrence of additional Ph-positive CML at diagnosis been accepted
universally
cytogenetic abnormalities in in the chronic phase has not
as heralding
the onset of advanced
stages of CML, although a change in karyotype during the course of the disease is considered a sign of disease progression [13,14]. However, Sokal et al. have shown that at z years after diagnosis, patients with additional cytogenetic abnormalities at presentation had an annual death rate approximately 40% higher than that seen with patients without such abnormalities [El. While TO-80% of patients entering blastic crisis show cytogenetic evolution, there has not been shown to be a specific karyotypic pattern correlating with the phenotypic expression of the blast crises, other than isochromosome of the long arm of chromosome 17 [i(lip)], which is seen with the myeloid blastic phase. In a series from the M.D. Anderson Cancer Center, patients with lymphoid transformation tended to have a lower incidence of trisomy 8 and of isochromosome 17, compared with those patients who evolved into myeioid or undifferentiated blastic crises [16]. The new CML Synthesis Prognostic Staging System supports the concept of shortened survival with cytogenetic clonal evolution but does not consider additional cytogenetic abnormalities at diagnosis a poor prognostic sign [v]. In addition, there are several case reports of patients with myeloid blastic crises whose cytogenetic pattern evolved into “characteristic” patterns associated with specific FAB ANLL subtypes. In each case, the phenotypic expression of the blast crises corresponded to its ANLL subtype [18-241. The t(11;14)(ql$q32) abnormality has been reported in a number of lymphoproliferative disorders. In association with B-CLL [25], an increased frequency of patients with prolymphocytic transformation has been reported in association with a rearrangement of the bcl-1 locus [26].The t(11,14) has been reported in diffuse small- and large-cell B-cell lymphomas, as well as in the mantle zone/intermediate lymphocytic lymphomas [27]. In multiple myeloma [28], the translocation has also been noted with bcl-1 gene rearrangements [29], At present, we are unable to determine the significance of these cytogenetic findings. The patient presented in hematologically typical chronic phase CML. There is no evidence of a monoclonal lymphoid disorder in this patient, i.e., lack of a clonal population of cells by Southern blot analyses of immunoglobulin heavy gene, T-cell B-receptor gene, and bcl-1 gene rearrangements. It will require the study of additional patients with the combined chromosomal translocations to ascertain whether a clonal lymphoid population might emerge at the time of disease progression.
lymphomas.
Am J Path01
5. Seabright M (1971): A rapid technique for human chromosomes. Lancet ii:971. 6. Gillespie DH, Cuddy K, Kolbe T, Marks DI (1994): Dissolve and capture: a strategy for analyzing mRNA in blood. Nature 367:390-391. z
Thompson JD, Bmdsky I, Yunis J (1992): Molecular quantification of residual disease in chronic myelogenous leukemia after bone marrow transplantation. Blood 79:1629-1635.
8. Korsmeyer S (1987): Antigen receptor genes as molecular markers of lymphoid neoplasms. J Clin Invest 79:1291-1295. 9. Durst M, Cmce CM, Gissman L, Schwartz E, Huebner K (1987): Papillomavirus sequences integrate near cellular oncogenes in some cervical carcinomas. Pmc Nat1 Acad Sci USA 84:1070-l(n4. 10. Feinberg AP, Vogelstein B (1983): A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 132:6-13. 11. Tsujimoto Y, Yunis J, Onorato-Showe L, E&son J, Nowell PC, Cmce CM (1984): Molecular cloning of the chmmosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chmmosome translocation. Science 224:1403-1406. 12. Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (1984): Cloning of the cbmmosome breakpoint of neoplastic B cells with the t(11;14) chromosome translocation. Science 224:1097-1099. 13. Whang-Peng J, Canellos GP, Carbone PP, Tjio JH (1968): Clinical implications of cytogenetic variants in chronic myelocytic leukemia. Blood 32:755-766. 14. Krulik M, Smadja N, De Gramont A, Gonzales-Canali G, Audebert AA, Dray C, Brissaund P, Debray J (1987): Sequential karyotypic study on Ph-positive chronic myelocytic leukemia; significance of additional chromosomal abnormalities during disease evolution. Cancer 60:974-979. 15. Sokal JE, Gomez GA, Baccarani M, Tura S, Clarkson BD, Cervantes F, Rozman C, Carbonell F, Angar B, Heimpel H, Nissen N, Robertson JE (1988): Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome positive chronic granulocytic leukemia. Blood 72: 294-298. 16. Derderian PM, Kantarjian HM, Talpaz M, O’Brien S, Cork A, Estey E, Pierce S, Keating M (1993): Chronic Myelogenous Leukemia in the lymphoid blastic phase: characteristics, treatment response and prognosis. Am J Med 94:69-74. 1%
Kantarjian HM, Keating MJ, Smith TL, Talpaz M, McCredie KB (1990): Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia. Am J Med 88:1-8.
18. Heim S, Christensen BE, Fioretos T, Sorensen A-G, Pedersen NT (1992): Acute myelomonocytic leukemia with inv(16)(pl3q22) complicating Philadelphia chromosome positive chronic myeloid leukemia. Cancer Genet Cytogenet 59:35-38. 19. Mecucci C, Noens L, Aventin A, Testoni N, Van Den Berghe H (1988): Philadelphia-positive acute myelomonocytic leukemia with inversion of chromosome 16 and eosinophils. Am J Haematol 27:69-71. 20. Li Y-S, Hayhoe FGJ (1988): Phi chromosome positive acute myelomonocytic leukaemia with inverted chromosome 16. Br J Haematol 69:576.
REFERENCES Nowell PC, Hungerford DA (1960): A minute chromosome human chronic granulocytic leukemia. Science 132:1497.
and non-Hodgkin’s
et al.
in
Rowley JD (1973): A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine flourescence and Giemsa staining. Nature 243:290-293. Hild F, Fonatsch C (1990): Cytogenetic peculiarities in chronic myelogenous leukemia. Cancer Genet Cytogenet 47:197-2X7. Athan E, Foitl DR, Knowles DM (1991): bcl-1 rearrangement: frequency and clinical significance among B-cell chronic lympho-
21. Berger R, Bernheim A, Daniel M-T, Flandrin G (1983): t(15;17) in a promyelocytic form of chronic myeloid leukemia blastic crisis. Cancer Genet Cytogenet 8:149-152. 22. Hogge DE, Misawa S, Schiffer CA, Testa JR (1984): Promyelocytic blast crisis in chronic granulocytic leukemia with 15;17 translocation. Leukemia Res 8:1019-1023. 23. Lai J-L, Fenaux P, Zandecki M, Savarv T-B, Estienne M-H, louet J-P, Bauters F, Deminatti M (1987): Pr&yelocytic blast crisis of Philadelphia-positive thrombocythemia with translocations (9;22) and (15;17). Cancer Genet Cytogenet 29:311-314.
t(11;14)
Translocation
27
in CML
24. Louwagie AC, Mecucci C, Criel A, Van Hoof A, Van Den Berghe H (1987): Variant translocation t(l5q;ljp) accompanying a promyelocytic accelerated phase of Ph-positive chronic myeloid leukemia. Cancer Genet Cytogenet 28:349-352.
2%
Leroux D, Le Marc’Hadour F, Gressin R, Jacob MC, Keddari E, Monteil M, Caillot P, Jalbert P, Sotto JT (1991): Non-Hodgkin’s lymphomas with t(11;14)(q13;q32): a subset of mantle zone/ intermediate lymphocytic lymphoma? Br J Haematol77:346-353.
25. Nowell PC, Shankey TV, Finan J, Guerry D, Besa E (1981): Pmliferation, differentiation, and cytogenetics of chronic leukemia B lymphocytes cultured with mitomycin-treated normal cells. Blood 57~444-451.
28. van den Berghe H, Vermaelen K, Louwagie A, Criel A, Mecucci C, Vaerman JP (1984): High incidence of chromosomal abnormalities in IgG3 myeloma. Cancer Genet Cytogenet 11:381-387.
26. Newman R, Davey F, Kornfeld SB, Collins H, Brabyn C, Bloomfield CD, Royston I (1990): Correlation of immunophenotype and bcl-1 gene rearrangements with morphology in B cell chronic lymphocytic leukemia (abstract). Blood 76(suppl 1):304a.
29. Meeker TC, Grimaldi JC, O’Rourke R, Louie E, Juliusson G, Einhorn S (1989): An additional breakpoint region in the bcl-1 locus associated with the t(11;14)(q13;q32) translocation in Blymphocyte malignancy. Blood 74:1801-1806.