Trisomy 14q in Myelodysplastic Syndromes P. H. Pinkerton, Betty London, I. D. DubS, and J. S. Senn
ABSTRACT: Two cases of myelodysplastic syndrome are described, both showing functional trisomy of the long arm of chromosome 14, supporting the concept that amplification of genes on chromosome 14 is associated with myeloproliferative and related diseases.
INTRODUCTION Trisomy 14 has been identified as an isolated or single cytogenetic abnormality in several proliferative m y e l o i d disorders, including one case of " p r e l e u k e m i a " [1]. Recently, three cases of acute n o n l y m p h o b l a s t i c leukemia (ANLL) with trisomy 14q as a single cytogenetic abnormality have been described, either with i(14q) or + 14 [2]. The presence of trisomy 14 as an isolated cytogenetic finding in other malignant or p r e m a l i g n a n t disorders is exceedingly rare [3, 4]. We report here two cases of myelodysplastic s y n d r o m e in w h i c h a cell line with trisomy 14q as the only cytogenetic abnormality was present in the bone marrow.
CASE REPORTS
Patient 1
This 74-year-old male presented with a 5-month history of lethargy, anemia, and one e p i s o d e of epistaxis. He had received transfusions of red blood cells on two occasions during the 5 months. There was no past history of hematologic significance, and apart from mucosal pallor, there were no relevant physical findings. Peripheral blood e x a m i n a t i o n s h o w e d hemoglobin 77g/L; mean cell volume 107 fl; white blood cells 9.2 × 109/L (neutrophils 53%; eosinophils 18%; basophils 7%; l y m p h o c y t e s 20%; monocytes 2%); and platelets 1044 x 109/L. The blood film showed anisopoikilocytosis w i t h oval macrocytes, eosinophilia with atypical forms, basophilia, and occasional giant platelets. The bone marrow showed dysplastic erythropoiesis with karyorrhexis and binucleate and megaloblastic forms. Granulopoiesis was active, with a relative decrease in mature forms, and basophils and atypical eosinophil precursors were prominent. Megakaryocytes were increased, with dysplasia and nuclear hyposegmentation. A diagnosis of p r i m a r y m y e l o d y s p l a s t i c syndrome was made (FAB type "refractory anemia"). From the Departments of LaboratoryHaematology(P. H. P., B. L.) and Medicine (J. S. S.), Sunnybrook Medical Centre and the University of Toronto Teaching Hospitals' Cancer Cytogenetics Unit (I. D. D.), Department of Pathology, University of Toronto, Ontario, Canada. Address reprint requests to: Dr. P. H. Pinkerton, Department of Laboratory Haematology, Sunnybrook Medical Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. Received January 5, 1990; accepted February 5, 1990.
113 © 1990 Elsevier Science Publishing Co., lnc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 49:113-116 (1990) 0165-4608/90/$3.50
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P.H. Pinkerton et al.
.A.
13
14
15
B
13
14
C
13
14
15
15
~J~ I
13
Figure 1 Abnormal chromosomes in patients 1 and 2. (A) D group chromosomes from the marrow of patient 1 showing i(14q). (B) D group chromosomes from the marrow of patient 2 showing an extra copy of chromosome 14 from the proposed myelodysplastic cell line. (C) Chromosomes 1 and 13 from the marrow of patient 2 showing translocation of material from 13q to lp, along with the normal homologues, from the proposed leukemic cell line.
Cytogenetic analysis of bone marrow using G-banding methods on direct preparations and after 24 hours culture revealed two cell lines, one 46,XY (18 cells) and the other 46,XY,i(14q) (11 cells) as illustrated in Figure 1A. The patient was treated with intermittent busulphan and blood transfusion. He died in June 1988 of intercurrent cardiovascular disease. Patient 2
A 40-year-old female presented in December 1988 with a history of several months progressive fatigue. She was referred for hematologic investigation as a result of a brief febrile illness and pallor. Peripheral blood examination revealed hemoglobin 40 g/L; mean cell volume 106 fl; white blood cells 4.2 x 109/L; (neutrophils 52%; lymphocytes 44%; monocytes 4%; occasional erythroblasts seen); and platelets 127 × 109/L. The blood film showed anisopoikilocytosis, ovalocytes, macro-ovalocytes, and hypogranular neutrophils. The bone marrow was hypercellular. Erythropoiesis was hyperplastic, with dysplastic features, megaloblastic forms, basophilic stippling, impaired hemoglobinization, and moderate numbers of ringed sideroblasts. Granulopoiesis was reduced, with a relative lack of mature forms and minor morphologic atypia. Blast cells were 15% of nucleated cells. Megakaryocytes were numerous, with dysplastic changes. A diagnosis of primary myelodysplastic syndrome was made (FAB type "refractory anemia with excess blasts"). Cytogenetic examination of the marrow showed three cell lines: 46,XX/46,XX,t(1;13)(p36;q14)/47,XX, + 14 (Table 1). A partial karyotype from the 47,XX, + 14 line is illustrated in Figure 1B, and from the 46,XX,t(1;13) line in Figure 1C. The patient received supportive transfusion therapy but no chemotherapy. In April 1989, leukopenia and more severe thrombocytopenia were observed, and bone marrow examination revealed 86% poorly differentiated blast cells, with marked reduction of mature cells. Very few cells stained for peroxidase or a-naphthyl acetate esterase. Occasional Auer rods were seen and immunophenotyping showed positivity for CD34 (66%) and CD13 (46%). A diagnosis of ANLL, FAB type M1, was made. Cytogenetic studies are summarized in Table 1. Cytotoxic therapy (cyclophosphamide, cytosine arabinoside, and vincristine) was given. Following this course of therapy, further marrow examination (May 11) showed
115
Trisomy 14q in Myelodysplastic Syndromes Table 1
Bone marrow findings (patient 2)
Date
Morphology
Dec. 30, 1988
Myelodysplasia (RAEB, 15% blasts)
Apr. 7, 1989
ANLL (FAB, M1) (86% blasts) Myelodysplasia (
ABSTRACT: Two cases of myelodysplastic syndrome are described, both showing functional trisomy of the long arm of chromosome 14, supporting the concept that amplification of genes on chromosome 14 is associated with myeloproliferative and related diseases.
INTRODUCTION Trisomy 14 has been identified as an isolated or single cytogenetic abnormality in several proliferative m y e l o i d disorders, including one case of " p r e l e u k e m i a " [1]. Recently, three cases of acute n o n l y m p h o b l a s t i c leukemia (ANLL) with trisomy 14q as a single cytogenetic abnormality have been described, either with i(14q) or + 14 [2]. The presence of trisomy 14 as an isolated cytogenetic finding in other malignant or p r e m a l i g n a n t disorders is exceedingly rare [3, 4]. We report here two cases of myelodysplastic s y n d r o m e in w h i c h a cell line with trisomy 14q as the only cytogenetic abnormality was present in the bone marrow.
CASE REPORTS
Patient 1
This 74-year-old male presented with a 5-month history of lethargy, anemia, and one e p i s o d e of epistaxis. He had received transfusions of red blood cells on two occasions during the 5 months. There was no past history of hematologic significance, and apart from mucosal pallor, there were no relevant physical findings. Peripheral blood e x a m i n a t i o n s h o w e d hemoglobin 77g/L; mean cell volume 107 fl; white blood cells 9.2 × 109/L (neutrophils 53%; eosinophils 18%; basophils 7%; l y m p h o c y t e s 20%; monocytes 2%); and platelets 1044 x 109/L. The blood film showed anisopoikilocytosis w i t h oval macrocytes, eosinophilia with atypical forms, basophilia, and occasional giant platelets. The bone marrow showed dysplastic erythropoiesis with karyorrhexis and binucleate and megaloblastic forms. Granulopoiesis was active, with a relative decrease in mature forms, and basophils and atypical eosinophil precursors were prominent. Megakaryocytes were increased, with dysplasia and nuclear hyposegmentation. A diagnosis of p r i m a r y m y e l o d y s p l a s t i c syndrome was made (FAB type "refractory anemia"). From the Departments of LaboratoryHaematology(P. H. P., B. L.) and Medicine (J. S. S.), Sunnybrook Medical Centre and the University of Toronto Teaching Hospitals' Cancer Cytogenetics Unit (I. D. D.), Department of Pathology, University of Toronto, Ontario, Canada. Address reprint requests to: Dr. P. H. Pinkerton, Department of Laboratory Haematology, Sunnybrook Medical Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. Received January 5, 1990; accepted February 5, 1990.
113 © 1990 Elsevier Science Publishing Co., lnc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 49:113-116 (1990) 0165-4608/90/$3.50
114
P.H. Pinkerton et al.
.A.
13
14
15
B
13
14
C
13
14
15
15
~J~ I
13
Figure 1 Abnormal chromosomes in patients 1 and 2. (A) D group chromosomes from the marrow of patient 1 showing i(14q). (B) D group chromosomes from the marrow of patient 2 showing an extra copy of chromosome 14 from the proposed myelodysplastic cell line. (C) Chromosomes 1 and 13 from the marrow of patient 2 showing translocation of material from 13q to lp, along with the normal homologues, from the proposed leukemic cell line.
Cytogenetic analysis of bone marrow using G-banding methods on direct preparations and after 24 hours culture revealed two cell lines, one 46,XY (18 cells) and the other 46,XY,i(14q) (11 cells) as illustrated in Figure 1A. The patient was treated with intermittent busulphan and blood transfusion. He died in June 1988 of intercurrent cardiovascular disease. Patient 2
A 40-year-old female presented in December 1988 with a history of several months progressive fatigue. She was referred for hematologic investigation as a result of a brief febrile illness and pallor. Peripheral blood examination revealed hemoglobin 40 g/L; mean cell volume 106 fl; white blood cells 4.2 x 109/L; (neutrophils 52%; lymphocytes 44%; monocytes 4%; occasional erythroblasts seen); and platelets 127 × 109/L. The blood film showed anisopoikilocytosis, ovalocytes, macro-ovalocytes, and hypogranular neutrophils. The bone marrow was hypercellular. Erythropoiesis was hyperplastic, with dysplastic features, megaloblastic forms, basophilic stippling, impaired hemoglobinization, and moderate numbers of ringed sideroblasts. Granulopoiesis was reduced, with a relative lack of mature forms and minor morphologic atypia. Blast cells were 15% of nucleated cells. Megakaryocytes were numerous, with dysplastic changes. A diagnosis of primary myelodysplastic syndrome was made (FAB type "refractory anemia with excess blasts"). Cytogenetic examination of the marrow showed three cell lines: 46,XX/46,XX,t(1;13)(p36;q14)/47,XX, + 14 (Table 1). A partial karyotype from the 47,XX, + 14 line is illustrated in Figure 1B, and from the 46,XX,t(1;13) line in Figure 1C. The patient received supportive transfusion therapy but no chemotherapy. In April 1989, leukopenia and more severe thrombocytopenia were observed, and bone marrow examination revealed 86% poorly differentiated blast cells, with marked reduction of mature cells. Very few cells stained for peroxidase or a-naphthyl acetate esterase. Occasional Auer rods were seen and immunophenotyping showed positivity for CD34 (66%) and CD13 (46%). A diagnosis of ANLL, FAB type M1, was made. Cytogenetic studies are summarized in Table 1. Cytotoxic therapy (cyclophosphamide, cytosine arabinoside, and vincristine) was given. Following this course of therapy, further marrow examination (May 11) showed
115
Trisomy 14q in Myelodysplastic Syndromes Table 1
Bone marrow findings (patient 2)
Date
Morphology
Dec. 30, 1988
Myelodysplasia (RAEB, 15% blasts)
Apr. 7, 1989
ANLL (FAB, M1) (86% blasts) Myelodysplasia (
