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A derivative chromosome 14 resulting in partial trisomy of chromosome 12 in B-cell chronic lymphocytic leukemia
A Derivative Chromosome 14 Resulting. in Partial Trisomy of Chromosome 12 in B-Cell Chronic Lymphocytic Leukemia
Trisomy 12 is the most common chromosomal aberration in patients with B-cell chronic lymphocytic leukemia (B-CLL). It was originally reported in 1980 with the first use of polyclonal B cell mitogens [1], and has since been described in approximately one third of patients [2]. Recent studies using fluorescence in situ hybridization (FISH) have revealed trisomy 12 in cases in which it was undetectable in the metaphase population [3]. Trisomy 12 is present in the malignant lymphocytes [4] and its presence has unfavorable prognostic implications [5]. The role of this lesion in pathogenesis remains unclear. We report a novel translocation in a B-CLL patient resulting in trisomy of the long arm of chromosome 12. In June, 1982 a 53-year-old female presented with a history of recurrent chest infection, but with no other significant symptoms. Clinical examination was normal. Her white cell count was 17 x 109/L of which 80% were lymphocytes, hemoglobin was 12.6 g/dL, and platelet count was 280 x 109/L. An IgG• paraprotein of 24.08 g/L (reference range 5-16 g/L) was detected in her serum. Bone marrow aspirate and trephine biopsy showed diffuse infiltration with
Figure I
small, mature lymphocytes, but no increase in plasma cells. She was diagnosed as Binet stage A chronic lymphocytic leukemia. No treatment was given at this time. Six months later, although remaining asymptomatic, she had developed axilliary and inguinal lymphadenopathy. Her hemoglobin had fallen to 6.1 g/dL, with no evidence of hemolysis, platelets were 270 x 109/L, and her WCC had risen to 46 x 109/L. Of these, 68% were mature lymphocytes, with 38% forming mouse rosettes. These findings indicated progression to Binet stage C B-CLL. She was treated with blood transfusion and a short course of steroids, and has subsequently required intermittent courses of chemotherapy, including cyclophosphamide, vincristine, prednisilone (CVP), and chlorambucil, to control significant rises in her WCC up to 300 x 109/L. Her WCC response to chemotherapy has remained sensitive throughout her 10-year treatment span, and she is currently alive and well. In August 1992, when her hematological parameters were Hb 14.1 g/dL, WCC 14.3 x 109/L, plts 1 7 7 × 109/L, and her IgGK paraprotein was unchanged, cytogenetic analysis was performed on peripheral blood using standard methods. The
G-bandedkaryotypeshowing the der(14)t(12;14)(q10;q10).
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| 159 © 1994 Elsevier Science Inc. 655 A v e n u e of the Americas, N e w York, NY 10010
Cancer Genet Cytogenet 7 6 : 1 5 9 - 1 6 0 (1994) 0165-4608/94/$07.00
160
A. McManus et al.
mitogens used were TPA (50 ng/mL) and PHA (10 ttg/mL). In the TPA cultures, 33% of the metaphases were karyotyped as 46,XX,der(14)t(12;14)(q10;q10) (Fig. 1). No PHA-stimulated cultures exhibited an abnormal karyotype. In addition, her peripheral blood l y m p h o c y t e s were s h o w n to be predominantly monoclonal B cells expressing an M)~ phenotype and flow cytometric analysis revealed 5 7% of the lymphocytes coexpressed CD5 and CD19. Trisomy 12 presumably exerts an effect through gene dosage, and several reports of partial trisomy involving 12q suggest that the critical trisomic region associated with B-CLL is situated on the long arm (2). This case provides further support to this hypothesis that one, or several, genes located on 12q contribute to the neoplastic characteristics of B-CLL. Advanced Binet stage, high WCC, short lymphocyte doubling time, and clonal cytogenic lesions are regarded as poor prognostic factors in B-CLL (6). The p r o l o n g e d survival of this patient, despite the presence of these adverse factors, m a y indicate that other parameters, such as her c o n t i n u e d chemosensitivity, are more significant in the biology of her disease.
ZUREENA R. DESAI
Department of Haematology Belfast City Hospital Belfast. N. Ireland.
REFERENCES 1. Gahrton G, Robert K-H, Friberg K, Zech L, Bird AG (1980): Nonrandom chromosomal aberrations in chronic lymphocytic leukaemia revealed by polyclonal B-cell-mitogenstimulation. Blood 56:640-647. 2. Juliusson G, Gahrton G (1990}: Chromosome aberrations in B-cell chronic lymphocytic leukemia. Pathogenetic and clinical implications. Cancer Genet Cytogenet 45:143-160. 3. Que TH, Marco JG, Ellis J, Matutes E, Brito Babapulle V, Boyle S, Catovsky D (1993): Trisomy 12 in chronic lymphocytic leukemia detected by fluorescence in situ hybridization: Analysis by stage, immunophenotype, and morphology. Blood 82:571-575. 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.
Department of Haematology Queen's University of Belfast Royal Victoria Hospital Belfast gr12 6BA. N. Ireland.
5. Juliusson G, Oscier D, Fitchett M, Ross FM, Stockdill G, Mackie MJ, Parker AC, Castoldi GL, Cueno A, Knuutila S, Elonen E, Gahrton G (1990): Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med 323:720-724.
*Current address: Molecular Cytogenetics, The Institute of Cancer Research, Block F 5 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, England.
6. Dighiem G, Tmvade P, Chevret S, Fenaux P, Chastang C, Binet J-L, and the French Cooperative Group on CLL (1991): B-cell chronic lymphocytic leukemia: present status and future directions. Blood 78:1901-1914.
AIDAN P. McMANUS* KAREN E. M. BAILIE HILARY JESS
Trisomy 12 is the most common chromosomal aberration in patients with B-cell chronic lymphocytic leukemia (B-CLL). It was originally reported in 1980 with the first use of polyclonal B cell mitogens [1], and has since been described in approximately one third of patients [2]. Recent studies using fluorescence in situ hybridization (FISH) have revealed trisomy 12 in cases in which it was undetectable in the metaphase population [3]. Trisomy 12 is present in the malignant lymphocytes [4] and its presence has unfavorable prognostic implications [5]. The role of this lesion in pathogenesis remains unclear. We report a novel translocation in a B-CLL patient resulting in trisomy of the long arm of chromosome 12. In June, 1982 a 53-year-old female presented with a history of recurrent chest infection, but with no other significant symptoms. Clinical examination was normal. Her white cell count was 17 x 109/L of which 80% were lymphocytes, hemoglobin was 12.6 g/dL, and platelet count was 280 x 109/L. An IgG• paraprotein of 24.08 g/L (reference range 5-16 g/L) was detected in her serum. Bone marrow aspirate and trephine biopsy showed diffuse infiltration with
Figure I
small, mature lymphocytes, but no increase in plasma cells. She was diagnosed as Binet stage A chronic lymphocytic leukemia. No treatment was given at this time. Six months later, although remaining asymptomatic, she had developed axilliary and inguinal lymphadenopathy. Her hemoglobin had fallen to 6.1 g/dL, with no evidence of hemolysis, platelets were 270 x 109/L, and her WCC had risen to 46 x 109/L. Of these, 68% were mature lymphocytes, with 38% forming mouse rosettes. These findings indicated progression to Binet stage C B-CLL. She was treated with blood transfusion and a short course of steroids, and has subsequently required intermittent courses of chemotherapy, including cyclophosphamide, vincristine, prednisilone (CVP), and chlorambucil, to control significant rises in her WCC up to 300 x 109/L. Her WCC response to chemotherapy has remained sensitive throughout her 10-year treatment span, and she is currently alive and well. In August 1992, when her hematological parameters were Hb 14.1 g/dL, WCC 14.3 x 109/L, plts 1 7 7 × 109/L, and her IgGK paraprotein was unchanged, cytogenetic analysis was performed on peripheral blood using standard methods. The
G-bandedkaryotypeshowing the der(14)t(12;14)(q10;q10).
S
1!
IZ
|g
0
5
II 16
||
17
16
Ul
| 159 © 1994 Elsevier Science Inc. 655 A v e n u e of the Americas, N e w York, NY 10010
Cancer Genet Cytogenet 7 6 : 1 5 9 - 1 6 0 (1994) 0165-4608/94/$07.00
160
A. McManus et al.
mitogens used were TPA (50 ng/mL) and PHA (10 ttg/mL). In the TPA cultures, 33% of the metaphases were karyotyped as 46,XX,der(14)t(12;14)(q10;q10) (Fig. 1). No PHA-stimulated cultures exhibited an abnormal karyotype. In addition, her peripheral blood l y m p h o c y t e s were s h o w n to be predominantly monoclonal B cells expressing an M)~ phenotype and flow cytometric analysis revealed 5 7% of the lymphocytes coexpressed CD5 and CD19. Trisomy 12 presumably exerts an effect through gene dosage, and several reports of partial trisomy involving 12q suggest that the critical trisomic region associated with B-CLL is situated on the long arm (2). This case provides further support to this hypothesis that one, or several, genes located on 12q contribute to the neoplastic characteristics of B-CLL. Advanced Binet stage, high WCC, short lymphocyte doubling time, and clonal cytogenic lesions are regarded as poor prognostic factors in B-CLL (6). The p r o l o n g e d survival of this patient, despite the presence of these adverse factors, m a y indicate that other parameters, such as her c o n t i n u e d chemosensitivity, are more significant in the biology of her disease.
ZUREENA R. DESAI
Department of Haematology Belfast City Hospital Belfast. N. Ireland.
REFERENCES 1. Gahrton G, Robert K-H, Friberg K, Zech L, Bird AG (1980): Nonrandom chromosomal aberrations in chronic lymphocytic leukaemia revealed by polyclonal B-cell-mitogenstimulation. Blood 56:640-647. 2. Juliusson G, Gahrton G (1990}: Chromosome aberrations in B-cell chronic lymphocytic leukemia. Pathogenetic and clinical implications. Cancer Genet Cytogenet 45:143-160. 3. Que TH, Marco JG, Ellis J, Matutes E, Brito Babapulle V, Boyle S, Catovsky D (1993): Trisomy 12 in chronic lymphocytic leukemia detected by fluorescence in situ hybridization: Analysis by stage, immunophenotype, and morphology. Blood 82:571-575. 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.
Department of Haematology Queen's University of Belfast Royal Victoria Hospital Belfast gr12 6BA. N. Ireland.
5. Juliusson G, Oscier D, Fitchett M, Ross FM, Stockdill G, Mackie MJ, Parker AC, Castoldi GL, Cueno A, Knuutila S, Elonen E, Gahrton G (1990): Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med 323:720-724.
*Current address: Molecular Cytogenetics, The Institute of Cancer Research, Block F 5 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, England.
6. Dighiem G, Tmvade P, Chevret S, Fenaux P, Chastang C, Binet J-L, and the French Cooperative Group on CLL (1991): B-cell chronic lymphocytic leukemia: present status and future directions. Blood 78:1901-1914.
AIDAN P. McMANUS* KAREN E. M. BAILIE HILARY JESS