A Case of Myelodysplastic Syndrome with Abnormal Megakaryocytes and ins(8;3)(q24;q21q26) M. Bachy-Delhomme, M. F. Bertheas, J. Jaubert, P. Calmard, C. Vasselon, J. Reynaud, and C. P. Brizard
We report a 56-year-old male patient with refractory anemia with excess of blasts in transformation (RAEB-T) who had an ins(8;3)(q24;q21q26) as the sole chromosome abnormality in bone marrow (BM) cells. The findings of disturbed thrombocytopoiesis with n u m e r o u s micromegakaryocytes s u g g e s t that it could be a variant of the classic ins(3;3)(q26;q21q26) described in hematologic malignancies with abnormal thrambopoiesis.
ABSTRACT:
INTRODUCTION Myelodysplastic syndrome (MDS) is a group of disorders affecting myeloid cells and often termed preleukemia because patients with MDS have an increased risk of developing leukemia. As proposed by the French-American-British (FAB) Cooperative Leukemia Group [1], these syndromes are grouped into five distinct entities: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), chronic myelomonocytic leukemia (CMMoL), and refractory anemia with excess blasts in transformation (RAEB-T). MDS represent clonal abnormalities of hematopoietic stem ceils that may undergo leukemic proliferation. Chromosome aberrations were identified with banding techniques in patients with MDS. The most common changes described are: del(5q), del(7q), monosomy 7, trisomy 8, and del(20q) [2]. Structural aberrations rarely occur as the single abnormality [3]. Rearrangements affecting the long arm of chromosome 3 have been described in acute nonlymphocytic leukemias (ANLL), chronic myeloid leukemia (CML), and MDS with abnormal megakaryocyte morphology and/or increased or preserved platelet production [4-14]. We report a patient with refractory anemia with RAEB-T and ins(8;3)(q24;q21q26) as the sole chromosomal abnormality. The patient showed abnormal thrombopoiesis with increased numbers of megakaryocytes and numerous micromegakaryocytes. CASE REPORT
A 56-year-old man had astenia and anorexia in July 1988. He had neither hepatosplenomegaly nor lymph node enlargement. The hematologic data were as follows: From the Department of Hematology-Cytogenetics, Centre H6pitalier et Universitaire de Saint Etienne, France.
Address reprint requests to: Dr. M. F. Bertheas, Department of Hematology-Cytogenetics, H6pital Nord Saint Etienne, 42277 Saint Priest en Jarez, France. Received September 28, 1990, accepted December 26, 1990.
31 © 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York~ NY 10010
Cancer Genet Cytogenet 55:31 34 (1991) 0165-4608/91/$03.50
32
M. Bachy-Delhomme et a l
Table 1
Cytogenetics results of sequential 24-hour u n s t i m u l a t e d bone marrow cultures
Date
Normal mitoses
Mitoses with ins(8;3)
7/19/88 9/15/88 10/18/88 1/30/89 3/28/89 4/11/90
6 1 -3 2 1
7 11 4 4 6 10
hemoglobin (Hb) 33 g/L, hematocrit (Hct) 10.8%, m e d i u m cell v o l u m e (MCV) 117 fl, platelet count 58.109/L, white blood cell count (WBC) 2.9.109/L with 35% n e u t r o p h i l s (PN), 52% lymphocytes, and 13% monocytes. Serum iron, transferrin, lysozyme were normal. Bone marrow (BM) aspirate showed normal cellularity with dyserythropoiesis without sideroblasts. Granulopoiesis showed a left shift with 25% blasts and marked dysplastic features. The megakaryocytes were dysplastic with m a n y small forms and micromegakaryocytes with h y p o l o b u l a t e d nuclei. The diagnosis was RAEB-T. The patient received low-dose cytosine arabinoside (ara-c) until April 1989 and b i m o n t h l y blood transfusions. Persistent blasts (2-25%) were noted in sequential BM aspirates. No complete remission was achieved. In April 1990, the patient had hepatosplenomegaly. The hematologic data were Hb level of 80 g/L, WBC count of 6 x 109/L, PN 47%, l y m p h o c y t e s 36%, monocytes 3%, blasts 9%, myelocytes 5%, and platelet count of 15 x 109/L. Bone marrow e x a m i n a t i o n showed persistent marked features of dysgranulopoiesis with 40% blasts. A b n o r m a l megakaryopoiesis and n u m e r o u s micromegakaryocytes were still present.
Cytogenetic Analysis The patient's BM was cytogenetically investigated on six occasions between July 1988 and April 1990. Cells were cultured in RPMI 1640 for 24 hours before standard harvesting and RHA and QPQ banding. The karyotype was described according to the International System for H u m a n Cytogenetic Nomenclature [15]. The results of sequential cytogenetic studies are shown in Table 1. The chromosome rearrangement was described as an insertion between chromosomes 8 and 3, ins(8;3)(q24;q21q26) (Fig. 1). Cells with a normal karyotype were present in all but one examination.
DISCUSSION An ins(8;3)(q24;q2 lq26) is reported in a patient with RAEB-T and abnormal megakaryocytes. Rearrangements of chromosome 8q24 have rarely been described in MDS; only three cases have been listed by Mitelman [3]. The c-myc oncogene is m a p p e d to c h r o m o s o m e 8q24. The breakpoint of our patient's rearrangement may actually be far from the c-myc locus, and molecular studies of the patient will be performed. Mertens et al. [16] reported a case of MDS with a t(3;8)(q26;q24). The patient had an acquired idiopathic sideroblastic anemia that evolved to RAEB and normal or slightly elevated platelet counts and abnormal megakaryocytes. Jenkins et al. [4] recently r e v i e w e d 12 cases of acute leukemia with abnormal thrombopoiesis and rearrangements of chromosome 3. Among the 12 patients, one had secondary ANLL with an ins(6;3)(p21;q21q26.2). His platelet count was increased, and he showed no megakary-
MDS with Abnormal Megakaryocytes
33
Figure 1 R-banded karyotype showing ins (8;3)(q24; q21q26). (Arrows indicate rearranged chromosomes). Inset: Partial Q-banded karyotype showing pairs 3 and 8.
ocyte abnormalities. Rearrangements of chromosome 3 involving 3q21 and 3q26 have been observed in hematologic malignancies with disturbed thrombopoiesis, suggesting that genes on 3q might be involved in megakaryocyte maturation and platelet production [17]. Recent review of patients reported in the literature [4-14, 18] showed no evidence of a gene regulating thrombopoietin production on chromosome 3q. Several genes coding for proteins important for hematopoiesis have been m a p p e d on chromosome 3q, such as transferrin (TF), transferrin receptor (TF-R), and ceruloplasmin [19]. In a recent report [20], Abe et al. suggested that TF-R is not involved in the pathogenesis of hematologic diseases with 3q abnormalities. Studies c o m b i n i n g cytogenetic and molecular techniques are warranted in these patients to determine the exact role of rearrangement of chromosome 3.
REFERENCES 1. Bennett JM, Catovsky D, Daniel M-T, Flandrin G, Galton DAG, Gralnik HR, Sultan C (1982): Proposals for the classification of the myelodysplastic syndromes. Br J Haemato151:189-199. 2. Yunis JJ, Lobell M, Arnesem MA, Oken MM, Mayer MG, Rydell RE, Brunning D (1988): Refined chromosome study helps define prognostic subgroups in most patients with primary myelodysplastic syndrome and acute myelogenous leukaemia. Br J Haematol 68:189-194. 3. Mitelman F (1987): Catalog of Chromosome Aberrations in Cancer. Alan R. Liss, New York, pp. 347-351. 4. Jenkins RB, Tefferi A, Solberg LA, Dewald GW (1989): Acute leukemia with abnormal thrombopoiesis and inversions of chromosome 3. Cancer Genet Cytogenet 39:167-179. 5. Sweet DH, Golomb HM, Rowley JD, Vardiman JM (1979): Acute myelogenous leukemia and thombocytopenia associated with an abnormality of chromosome no 3. Cancer Genet Cytogenet 1:33-37.
34
M. B a c h y - D e l h o m m e et al.
6. Bernstein R, Pinto MR, Behr A, Mendelow B (1982): Chromosome 3 abnormalities in acute nonlymphocytic leukemia (ANLL) with abnormal thrombopoiesis: Report of three patients with a " n e w " inversion anomaly and a further case of homologous translocation. Blood 60:613-617. 7. Mecucci C, Vermaelen K, Tricot G, Louwagie A, Michaux JL, Bosly A, Thomas J, Barbieri D, Van Den Berghe H (1983): 3 q - , 3q+ Anomaly in malignant proliferations in humans. Cancer Genet Cytogenet 9:367-381. 8. Pinto MR, King MA, Gross GD, Bezwoda WR, Fernandes-Costa F, Mendelow B, McDonald TP, Dowdle E (1985]: Acute megakaryoblastic leukaemia with 3q inversion and elevated thrombopoietin (TSF): an autocrine role for TSF? Br J Haematol 61:687-694. 9. Pintado T, Ferro MT, Roman CS, Mayayo M, Larana JG (1985): Clinical correlations of the 3q21; q26 cytogenetic anomaly: A leukemic or myelodysplastic syndrome with preserved or increased platelet production and lack of response to cytotoxic drug therapy. Cancer 55:535-541. 10. Norrby A, Ridell B, Swolin B, Westin J (1982): Rearrangement of chromosome no 3 in a case of preleukemia with thombocytosis. Cancer Genet Cytogenet 5:257-263. 11. Carbonell F, Hoelzer D, Thiel E, Bartl R (1982): Phi-positive CML associated with megakaryocytic hyperplasia and thombocythemia and an abnormality of chromosome no 3. Cancer Genet Cytogenet 6:153-161. 12. Bitter MA, Neilly ME, Le Beau HM, Pearson MG, Rowley JD (1985): Rearrangements of chromosome 3 involving bands 3q21 and 3q26 are associated with normal or elevated platelet counts in acute nonlymphocytic leukemia. Blood 66:1362-1370. 13. Gascoyne RD, Noble MC, Kalousek DK (1986): Translocation t(3;3)(q21;q26) and thombocytosis (Letter]. Cancer Genet Cytogenet 22:365. 14. Carroll AJ, Poom M-C, Robinson NC, Crist WM (1986): Sideroblastic anemia associated with thrombocytosis and a chromosome 3 abnormality. Cancer Genet Cytogenet 22:183-187. 15. ISCN (1985): An International System for Human Cytogenetic Nomenclature, Harden DG, Klinnger 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, New York, 1985). 16. Mertens F, Johansson B, Billstr0m R, Engquist L, Mitelman F (1987): A case of myelodysplastic syndrome with high platelet counts and a t(3;8)(q26;q24). Cancer Genet Cytogenet 27:1-4. 17. Helm S, Mitelman F (1987): Acute nonlymphocytic leukemia. In: S Helm, F Mitelman, eds.: Cancer Cytogenetics. New York: Alan R. Liss, pp. 65-110. 18. Walter TA, Morgan R, Ondreyco S, Sandberg AA (1990): Apparent duplication of inv(3)(q21q26) in one of five cases with inv(3) in myelodysplastic syndromes and acute leukemia. Am J Hematol 33:210-214. 19. Gusella JF, Wasmuth JJ (1987): Report of the committee on the genetic constitution ot chromosomes 3 and 4. Ninth International Workshop on Human Gene Mapping. Cytogenet Cell Genet 46:131. 20. Abe Y, Muta K, Yufu Y, Takahira H, Nishimura J, Nawata H (1990): The transferrin receptoi system is not involved in the pathogenesis of hematological disorders with 3q inversion. Am J Hematol 33:215-219.
We report a 56-year-old male patient with refractory anemia with excess of blasts in transformation (RAEB-T) who had an ins(8;3)(q24;q21q26) as the sole chromosome abnormality in bone marrow (BM) cells. The findings of disturbed thrombocytopoiesis with n u m e r o u s micromegakaryocytes s u g g e s t that it could be a variant of the classic ins(3;3)(q26;q21q26) described in hematologic malignancies with abnormal thrambopoiesis.
ABSTRACT:
INTRODUCTION Myelodysplastic syndrome (MDS) is a group of disorders affecting myeloid cells and often termed preleukemia because patients with MDS have an increased risk of developing leukemia. As proposed by the French-American-British (FAB) Cooperative Leukemia Group [1], these syndromes are grouped into five distinct entities: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), chronic myelomonocytic leukemia (CMMoL), and refractory anemia with excess blasts in transformation (RAEB-T). MDS represent clonal abnormalities of hematopoietic stem ceils that may undergo leukemic proliferation. Chromosome aberrations were identified with banding techniques in patients with MDS. The most common changes described are: del(5q), del(7q), monosomy 7, trisomy 8, and del(20q) [2]. Structural aberrations rarely occur as the single abnormality [3]. Rearrangements affecting the long arm of chromosome 3 have been described in acute nonlymphocytic leukemias (ANLL), chronic myeloid leukemia (CML), and MDS with abnormal megakaryocyte morphology and/or increased or preserved platelet production [4-14]. We report a patient with refractory anemia with RAEB-T and ins(8;3)(q24;q21q26) as the sole chromosomal abnormality. The patient showed abnormal thrombopoiesis with increased numbers of megakaryocytes and numerous micromegakaryocytes. CASE REPORT
A 56-year-old man had astenia and anorexia in July 1988. He had neither hepatosplenomegaly nor lymph node enlargement. The hematologic data were as follows: From the Department of Hematology-Cytogenetics, Centre H6pitalier et Universitaire de Saint Etienne, France.
Address reprint requests to: Dr. M. F. Bertheas, Department of Hematology-Cytogenetics, H6pital Nord Saint Etienne, 42277 Saint Priest en Jarez, France. Received September 28, 1990, accepted December 26, 1990.
31 © 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York~ NY 10010
Cancer Genet Cytogenet 55:31 34 (1991) 0165-4608/91/$03.50
32
M. Bachy-Delhomme et a l
Table 1
Cytogenetics results of sequential 24-hour u n s t i m u l a t e d bone marrow cultures
Date
Normal mitoses
Mitoses with ins(8;3)
7/19/88 9/15/88 10/18/88 1/30/89 3/28/89 4/11/90
6 1 -3 2 1
7 11 4 4 6 10
hemoglobin (Hb) 33 g/L, hematocrit (Hct) 10.8%, m e d i u m cell v o l u m e (MCV) 117 fl, platelet count 58.109/L, white blood cell count (WBC) 2.9.109/L with 35% n e u t r o p h i l s (PN), 52% lymphocytes, and 13% monocytes. Serum iron, transferrin, lysozyme were normal. Bone marrow (BM) aspirate showed normal cellularity with dyserythropoiesis without sideroblasts. Granulopoiesis showed a left shift with 25% blasts and marked dysplastic features. The megakaryocytes were dysplastic with m a n y small forms and micromegakaryocytes with h y p o l o b u l a t e d nuclei. The diagnosis was RAEB-T. The patient received low-dose cytosine arabinoside (ara-c) until April 1989 and b i m o n t h l y blood transfusions. Persistent blasts (2-25%) were noted in sequential BM aspirates. No complete remission was achieved. In April 1990, the patient had hepatosplenomegaly. The hematologic data were Hb level of 80 g/L, WBC count of 6 x 109/L, PN 47%, l y m p h o c y t e s 36%, monocytes 3%, blasts 9%, myelocytes 5%, and platelet count of 15 x 109/L. Bone marrow e x a m i n a t i o n showed persistent marked features of dysgranulopoiesis with 40% blasts. A b n o r m a l megakaryopoiesis and n u m e r o u s micromegakaryocytes were still present.
Cytogenetic Analysis The patient's BM was cytogenetically investigated on six occasions between July 1988 and April 1990. Cells were cultured in RPMI 1640 for 24 hours before standard harvesting and RHA and QPQ banding. The karyotype was described according to the International System for H u m a n Cytogenetic Nomenclature [15]. The results of sequential cytogenetic studies are shown in Table 1. The chromosome rearrangement was described as an insertion between chromosomes 8 and 3, ins(8;3)(q24;q21q26) (Fig. 1). Cells with a normal karyotype were present in all but one examination.
DISCUSSION An ins(8;3)(q24;q2 lq26) is reported in a patient with RAEB-T and abnormal megakaryocytes. Rearrangements of chromosome 8q24 have rarely been described in MDS; only three cases have been listed by Mitelman [3]. The c-myc oncogene is m a p p e d to c h r o m o s o m e 8q24. The breakpoint of our patient's rearrangement may actually be far from the c-myc locus, and molecular studies of the patient will be performed. Mertens et al. [16] reported a case of MDS with a t(3;8)(q26;q24). The patient had an acquired idiopathic sideroblastic anemia that evolved to RAEB and normal or slightly elevated platelet counts and abnormal megakaryocytes. Jenkins et al. [4] recently r e v i e w e d 12 cases of acute leukemia with abnormal thrombopoiesis and rearrangements of chromosome 3. Among the 12 patients, one had secondary ANLL with an ins(6;3)(p21;q21q26.2). His platelet count was increased, and he showed no megakary-
MDS with Abnormal Megakaryocytes
33
Figure 1 R-banded karyotype showing ins (8;3)(q24; q21q26). (Arrows indicate rearranged chromosomes). Inset: Partial Q-banded karyotype showing pairs 3 and 8.
ocyte abnormalities. Rearrangements of chromosome 3 involving 3q21 and 3q26 have been observed in hematologic malignancies with disturbed thrombopoiesis, suggesting that genes on 3q might be involved in megakaryocyte maturation and platelet production [17]. Recent review of patients reported in the literature [4-14, 18] showed no evidence of a gene regulating thrombopoietin production on chromosome 3q. Several genes coding for proteins important for hematopoiesis have been m a p p e d on chromosome 3q, such as transferrin (TF), transferrin receptor (TF-R), and ceruloplasmin [19]. In a recent report [20], Abe et al. suggested that TF-R is not involved in the pathogenesis of hematologic diseases with 3q abnormalities. Studies c o m b i n i n g cytogenetic and molecular techniques are warranted in these patients to determine the exact role of rearrangement of chromosome 3.
REFERENCES 1. Bennett JM, Catovsky D, Daniel M-T, Flandrin G, Galton DAG, Gralnik HR, Sultan C (1982): Proposals for the classification of the myelodysplastic syndromes. Br J Haemato151:189-199. 2. Yunis JJ, Lobell M, Arnesem MA, Oken MM, Mayer MG, Rydell RE, Brunning D (1988): Refined chromosome study helps define prognostic subgroups in most patients with primary myelodysplastic syndrome and acute myelogenous leukaemia. Br J Haematol 68:189-194. 3. Mitelman F (1987): Catalog of Chromosome Aberrations in Cancer. Alan R. Liss, New York, pp. 347-351. 4. Jenkins RB, Tefferi A, Solberg LA, Dewald GW (1989): Acute leukemia with abnormal thrombopoiesis and inversions of chromosome 3. Cancer Genet Cytogenet 39:167-179. 5. Sweet DH, Golomb HM, Rowley JD, Vardiman JM (1979): Acute myelogenous leukemia and thombocytopenia associated with an abnormality of chromosome no 3. Cancer Genet Cytogenet 1:33-37.
34
M. B a c h y - D e l h o m m e et al.
6. Bernstein R, Pinto MR, Behr A, Mendelow B (1982): Chromosome 3 abnormalities in acute nonlymphocytic leukemia (ANLL) with abnormal thrombopoiesis: Report of three patients with a " n e w " inversion anomaly and a further case of homologous translocation. Blood 60:613-617. 7. Mecucci C, Vermaelen K, Tricot G, Louwagie A, Michaux JL, Bosly A, Thomas J, Barbieri D, Van Den Berghe H (1983): 3 q - , 3q+ Anomaly in malignant proliferations in humans. Cancer Genet Cytogenet 9:367-381. 8. Pinto MR, King MA, Gross GD, Bezwoda WR, Fernandes-Costa F, Mendelow B, McDonald TP, Dowdle E (1985]: Acute megakaryoblastic leukaemia with 3q inversion and elevated thrombopoietin (TSF): an autocrine role for TSF? Br J Haematol 61:687-694. 9. Pintado T, Ferro MT, Roman CS, Mayayo M, Larana JG (1985): Clinical correlations of the 3q21; q26 cytogenetic anomaly: A leukemic or myelodysplastic syndrome with preserved or increased platelet production and lack of response to cytotoxic drug therapy. Cancer 55:535-541. 10. Norrby A, Ridell B, Swolin B, Westin J (1982): Rearrangement of chromosome no 3 in a case of preleukemia with thombocytosis. Cancer Genet Cytogenet 5:257-263. 11. Carbonell F, Hoelzer D, Thiel E, Bartl R (1982): Phi-positive CML associated with megakaryocytic hyperplasia and thombocythemia and an abnormality of chromosome no 3. Cancer Genet Cytogenet 6:153-161. 12. Bitter MA, Neilly ME, Le Beau HM, Pearson MG, Rowley JD (1985): Rearrangements of chromosome 3 involving bands 3q21 and 3q26 are associated with normal or elevated platelet counts in acute nonlymphocytic leukemia. Blood 66:1362-1370. 13. Gascoyne RD, Noble MC, Kalousek DK (1986): Translocation t(3;3)(q21;q26) and thombocytosis (Letter]. Cancer Genet Cytogenet 22:365. 14. Carroll AJ, Poom M-C, Robinson NC, Crist WM (1986): Sideroblastic anemia associated with thrombocytosis and a chromosome 3 abnormality. Cancer Genet Cytogenet 22:183-187. 15. ISCN (1985): An International System for Human Cytogenetic Nomenclature, Harden DG, Klinnger 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, New York, 1985). 16. Mertens F, Johansson B, Billstr0m R, Engquist L, Mitelman F (1987): A case of myelodysplastic syndrome with high platelet counts and a t(3;8)(q26;q24). Cancer Genet Cytogenet 27:1-4. 17. Helm S, Mitelman F (1987): Acute nonlymphocytic leukemia. In: S Helm, F Mitelman, eds.: Cancer Cytogenetics. New York: Alan R. Liss, pp. 65-110. 18. Walter TA, Morgan R, Ondreyco S, Sandberg AA (1990): Apparent duplication of inv(3)(q21q26) in one of five cases with inv(3) in myelodysplastic syndromes and acute leukemia. Am J Hematol 33:210-214. 19. Gusella JF, Wasmuth JJ (1987): Report of the committee on the genetic constitution ot chromosomes 3 and 4. Ninth International Workshop on Human Gene Mapping. Cytogenet Cell Genet 46:131. 20. Abe Y, Muta K, Yufu Y, Takahira H, Nishimura J, Nawata H (1990): The transferrin receptoi system is not involved in the pathogenesis of hematological disorders with 3q inversion. Am J Hematol 33:215-219.
