- Email: [email protected]
Monosomy 15 in chronic myelomonocytic leukemia
Cancer Genetics and Cytogenetics 134 (2002) 165–167
Short communication
Monosomy 15 in chronic myelomonocytic leukemia: description of a case and review of the literature Lourdes Zamoraa,*, Blanca Espineta,b, Marta Salidoa, Lourdes Florensab,c, Soledad Woessnerb, Carmen Pedrod, Sergi Serrtanoa,c, Francesc Soléa,b a
Laboratori de Citogenètica i Biologia Molecular, Departament de Patologia, Hospital del Mar, Pg Marítim, 25-29, Barcelona, 08003, Spain b Escola de Citologia Hematològica Soledad Woessner-IMAS, Pg Marítim, 25-29, Barcelona, 08003, Spain c Laboratori de Citologia Hematològica, Departament de Patologia, Hospital del Mar, IMAS, Pg Marítim, 25-29, Barcelona, 08003, Spain d Servei d’Hematologia Clínica, Hospital del Mar, IMAS, Pg Marítim, 25-29, Barcelona, 08003, Spain Received 2 October 2001; accepted 19 October 2001
Abstract
We report a 89-year-old female diagnosed with chronic myelomonocytic leukemia (CMMoL) presenting with a monosomy 15. To our knowledge, this is the second reported case of CMMoL with monosomy 15. On the other hand, monosomy 15 in complex karyotypes is a frequent chromosome aberration in myelodysplastic syndromes, particularly in refractory anemia with excess of blasts. © 2002 Elsevier Science Inc. All rights reserved.
1. Introduction
2. Case report
Chronic myelomonocytic leukemia (CMMoL) is a disease belonging to the group of common progenitor stem cell disorders. The defining feature of CMMoL is an absolute monocytosis in the peripheral blood (1109/L) in a myelodysplastic context. Dysmorphic signs usually affect the three cell lines. The bone marrow aspirate is hypercellular with predominant myeloid proliferation, increased monocytosis and moderate fibrosis. A useful datum for its diagnosis is an increased granulocyte macrophage colony formation (CFU-GM) growth in vitro without exogenous colony-stimulating activity [1]. The French–American–British (FAB) group suggested to segregate two CMMoL subtypes: myelodysplastic-CMMoL (white blood cell [WBC] count 13109/L) and myeloproliferative-CMMoL (WBC count 13109/L) [2]. The most frequently described cytogenetic abnormalities in CMMoL are those related to MDS, especially trisomy of chromosome 8, monosomy of chromosome 7, and 20q deletions. Translocation (5;12)(q33;p13) resulting in the PDGFR-TEL fusion gene can also be found. However, no single characteristic chromosome anomaly has been associated with CMMoL [3].
A 89-year-old woman was admitted to hospital for study of anemia. No visceromegaly was revealed by physical examination. Hematologic data showed: hemoglobin of 54 g/L, mean corpuscular volume (MCV) of 92.8 fL, platelets of 118109/L with dysmorphic signs and WBC of 20109/L (13% lymphocytes, 12% monocytes, 4% myelocytes, 25% metamyelocytes, 42% segmented neutrophils, 2% eosinophils and 2% blastic cells). Morphological anomalies were observed in neutrophils (diminution of primary granules and poor segmentation) and erythrocytes (anisocytosis and poikylocytosis). A hypercellular bone marrow aspiration showed a predominant myeloid proliferation (59% with 3% of blastic cells) and increased monocytosis. Granulocytic elements showed extreme dysgranulopoiesis, especially segmentation anomalies. Erythroid cells showed marked dyserythropoetic features with 8% of ringed sideroblasts. Megakaryocyte cells were normal. An excessively increased CFU-GM growth in vitro in the absence of supplementation with an exogenous source of colony-stimulating activity was found. No growth of erythroid and megakaryocyte progenitors was detected under the same conditions. Cytogenetic study was performed on a 24-hour nonstimulated culture of bone marrow following standard procedures. Twenty metaphases were analyzed on G-banded slides and karyotype was described according to the ISCN 1995 nomenclature [4]. Five metaphases presented a normal 46,XX karyotype and fifteen cells showed the presence of a
* Corresponding author. Tel.: 34-93-248-30-35; fax: 34-93-221-29-20. E-mail address: [email protected] (L. Zamora).
0165-4608/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S0165-4608(01)00 6 2 9 - X
166
L. Zamora et al. / Cancer Genetics and Cytogenetics 134 (2002) 165–167
Fig. 1. Bone marrow karyotype showing 45,XX,15.
45,XX,15 karyotype (Fig. 1). With all these data the diagnosis of CMMoL was established. The patient died 7 months after being diagnosed. 3. Discussion To our knowledge, this is the second reported CMMoL showing monosomy 15 as a sole abnormality [5]. The first case was described by the Group Français de Cytogénétique Hématologique in 1986 presenting with classical morphologic and hematologic features and a peripheral blood monocytosis ranging from 1 to 5109/L [6]. If the FAB group criteria are considered, it cannot be said if the two described cases belong to the same subtype because, although the case presented herein is included in the subtype called myeloproliferative-CMMoL with WBC count 13109/L [2], in the first described case by the French group there is no mention of the WBC count. The two reported cases have monosomy 15 in mosaicism, with a less frequent normal clone. Although there are only two described cases of monosomy 15 as a sole anomaly, monosomy 15 in complex karyotypes is a frequent event in myelodysplastic syndrome
(MDS) particularly in refractory anemia with excess of blasts (RAEB). In a review of the literature [5,7] we found 53 cases of MDS presenting monosomy 15 plus other cytogenetic abnormalities. Among them, there were 18 RAEB, 14 refractory anemias with excess of blasts in transformation (RAEB-t), six MDS not otherwise specificated, six refractory anemias, five refractory anemias with ringed sideroblasts and four CMMoL. Regarding monosomy 15 in CMMoL, the characteristics of these four CMMoL cases can be seen in Table 1. The most frequently involved chromosomes accompanying monosomy 15 in these subgroups were chromosomes 5, 7, 17, 12, and 18 (Table 2). Several oncogenes involved in myeloid lineage have been mapped on chromosome 15 such as PML (implicated in t(15;17)(q22;q21) characteristic of acute promyelocytic leukemia) and AF15q14 (involved in t(11;15)(q23;q14) found in acute myeloblastic leukemia with maturation). These genes could be candidate genes involved in the development of leukemia [9]. It is noticeable that trisomy 15, often associated with loss of Y chromosome as an age-related effect, is found in myeloid and lymphoid lineages MDS, acute nonlymphocytic leukemia,
Table 1 Monosomy 15 and CMMoL: Review of reported cases as a sole abnormality or accompanied by other cytogenetic aberrations [5] Monosomy 15 in CMMoL As a sole abnormality With other abnormalities
Authors
Karyotype
GFCH 1986 [6] Present case GFCH 1986 [6] Horike et al. 1994 [7] Collado et al. 1999 [8]
46,XX[3]/45,XX,15[45] 46,XX[5]/46,XX,15[15] 46,XY[2]/45,XX,5,7,t(5;7)(q21;q11),6,15,21,r,2mar[10] 46,XY,der(1;15)t(q?;q?),15[9] 45,X,add(Xq),1,del(5),11,17,add(18q)/ 43,X,Y,2,4,add(4)(q34),7,8,del(11)(q23),13,15,17
Boldface: monoscomy 15. Brackets indicate the number of studied metaphases. Abbreviations: AML, acute myeloblastic leukemia; GFCH, Group Français de Cytogénétique Hématologique.
Survival (months)
Transformation
51 6 1 23 9
AML — — — AML
L. Zamora et al. / Cancer Genetics and Cytogenetics 134 (2002) 165–167 Table 2 The most frequent abnormalities accompanying monosomy 15 and the number of patients affected Chromosome 5
7
12
17
18
Abnormality (the most frequently involved regions)
Number of patients
5 5q[q11q35] others 7 7q[q11q36] others 12 add(12p)[p11p12] others 17 add(17p)[p11p12] others 18 others
22 19 12 19 9 14 4 6 16 11 5 14 15 10
acute lymphocytic leukemia, chronic lymphocytic leukemia but it has been also reported in patients free of hematological malignancies [10,11]. In conclusion, with these data we cannot associate monosomy 15 with a special subtype of CMMoL, but it can be suggested that the mentioned chromosome could be involved in the development of a MDS. Acknowledgments This work has been supported in part by the grant FIS 01/424 from Ministerio de Sanidad y Consumo. The authors wish to thank Rosa Maria Vilà, Rosa Navarro and Maria Carmen Vela for their excellent technical assistance.
167
References [1] Florensa L, Woessner S, Lafuente R, Buxó J, Almarcha J, Marill MR, Sans-Sabrafen J. In vitro granulopoiesis in myelodysplastic syndromes (MDS) according to the FAB classification. In: Schmalzl F, Mufti GJ, editors. Myelodysplastic syndromes. Berlin: Springer, 1996, pp. 222–32. [2] Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick H, Sultan C, Cox C. The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 1994;87:746–54. [3] Vallespí T, Imbert M, Mecucci C, Preudhomme C, Fenaux P. Diagnosis, classification, and cytogenetics of myelodysplastic syndromes (review). Haematologica 1998;83:258–75. [4] ISCN. Guidelines for Cancer Cytogenetics, Supplement to An International System for Human Cytogenetic Nomenclature. Mitelman F, editor. Basel: S. Karger, 1995. [5] Mitelman F, Johansson B, Mertens F (eds.) Mitelman database of chromosome aberrations in cancer. Available at: http//cgap.nci.nih.gov/ Chromosomes/Mitelman. Accessed: September 7, 2001. [6] Group Français de Cytogénétique Hématologique. Cytogenetics of chronic myelomonocytic leukemia. Cancer Genet Cytogenet 1986; 21:11–30. [7] Horike S, Misawa S, Nakai H, Kaneko H, Yokota S, Taniwaki M, Yamane Y, Inazawa J, Abe T, Kashima K. N-ras mutation and karyotypic evolution are closely associated with leukemic transformation in myelodysplastic syndrome. Leukemia 1994;8:1331–6. [8] Collado R, Badia L, Garcia S, Sanchez H, Prieto F, Carbonell F. Chromosome 11 abnormalities in myelodysplastic syndromes. Cancer Genet Cytogenet 1999;114:58–61. [9] Huret, JS. Atlas of genetics and cytogenetics in oncology and haematology. Available at: http://www.infobiogen.fr/services/chromcancer. Accessed: September 17, 2001. [10] Smith A, Watson N, Sharma P. Frequency of trisomy 15 and loss of the Y chromosome in adult leukemia. Cancer Genet Cytogenet 1999; 114:108–11. [11] Sinclair EJ, Potter AM, Watmore AE, Fithcett M, Ross F. Trisomy 15 associated with loss of the Y chromosome in bone marrow: a possible new aging effect. Cancer Genet Cytogenet 1998;105:20–3.
Short communication
Monosomy 15 in chronic myelomonocytic leukemia: description of a case and review of the literature Lourdes Zamoraa,*, Blanca Espineta,b, Marta Salidoa, Lourdes Florensab,c, Soledad Woessnerb, Carmen Pedrod, Sergi Serrtanoa,c, Francesc Soléa,b a
Laboratori de Citogenètica i Biologia Molecular, Departament de Patologia, Hospital del Mar, Pg Marítim, 25-29, Barcelona, 08003, Spain b Escola de Citologia Hematològica Soledad Woessner-IMAS, Pg Marítim, 25-29, Barcelona, 08003, Spain c Laboratori de Citologia Hematològica, Departament de Patologia, Hospital del Mar, IMAS, Pg Marítim, 25-29, Barcelona, 08003, Spain d Servei d’Hematologia Clínica, Hospital del Mar, IMAS, Pg Marítim, 25-29, Barcelona, 08003, Spain Received 2 October 2001; accepted 19 October 2001
Abstract
We report a 89-year-old female diagnosed with chronic myelomonocytic leukemia (CMMoL) presenting with a monosomy 15. To our knowledge, this is the second reported case of CMMoL with monosomy 15. On the other hand, monosomy 15 in complex karyotypes is a frequent chromosome aberration in myelodysplastic syndromes, particularly in refractory anemia with excess of blasts. © 2002 Elsevier Science Inc. All rights reserved.
1. Introduction
2. Case report
Chronic myelomonocytic leukemia (CMMoL) is a disease belonging to the group of common progenitor stem cell disorders. The defining feature of CMMoL is an absolute monocytosis in the peripheral blood (1109/L) in a myelodysplastic context. Dysmorphic signs usually affect the three cell lines. The bone marrow aspirate is hypercellular with predominant myeloid proliferation, increased monocytosis and moderate fibrosis. A useful datum for its diagnosis is an increased granulocyte macrophage colony formation (CFU-GM) growth in vitro without exogenous colony-stimulating activity [1]. The French–American–British (FAB) group suggested to segregate two CMMoL subtypes: myelodysplastic-CMMoL (white blood cell [WBC] count 13109/L) and myeloproliferative-CMMoL (WBC count 13109/L) [2]. The most frequently described cytogenetic abnormalities in CMMoL are those related to MDS, especially trisomy of chromosome 8, monosomy of chromosome 7, and 20q deletions. Translocation (5;12)(q33;p13) resulting in the PDGFR-TEL fusion gene can also be found. However, no single characteristic chromosome anomaly has been associated with CMMoL [3].
A 89-year-old woman was admitted to hospital for study of anemia. No visceromegaly was revealed by physical examination. Hematologic data showed: hemoglobin of 54 g/L, mean corpuscular volume (MCV) of 92.8 fL, platelets of 118109/L with dysmorphic signs and WBC of 20109/L (13% lymphocytes, 12% monocytes, 4% myelocytes, 25% metamyelocytes, 42% segmented neutrophils, 2% eosinophils and 2% blastic cells). Morphological anomalies were observed in neutrophils (diminution of primary granules and poor segmentation) and erythrocytes (anisocytosis and poikylocytosis). A hypercellular bone marrow aspiration showed a predominant myeloid proliferation (59% with 3% of blastic cells) and increased monocytosis. Granulocytic elements showed extreme dysgranulopoiesis, especially segmentation anomalies. Erythroid cells showed marked dyserythropoetic features with 8% of ringed sideroblasts. Megakaryocyte cells were normal. An excessively increased CFU-GM growth in vitro in the absence of supplementation with an exogenous source of colony-stimulating activity was found. No growth of erythroid and megakaryocyte progenitors was detected under the same conditions. Cytogenetic study was performed on a 24-hour nonstimulated culture of bone marrow following standard procedures. Twenty metaphases were analyzed on G-banded slides and karyotype was described according to the ISCN 1995 nomenclature [4]. Five metaphases presented a normal 46,XX karyotype and fifteen cells showed the presence of a
* Corresponding author. Tel.: 34-93-248-30-35; fax: 34-93-221-29-20. E-mail address: [email protected] (L. Zamora).
0165-4608/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S0165-4608(01)00 6 2 9 - X
166
L. Zamora et al. / Cancer Genetics and Cytogenetics 134 (2002) 165–167
Fig. 1. Bone marrow karyotype showing 45,XX,15.
45,XX,15 karyotype (Fig. 1). With all these data the diagnosis of CMMoL was established. The patient died 7 months after being diagnosed. 3. Discussion To our knowledge, this is the second reported CMMoL showing monosomy 15 as a sole abnormality [5]. The first case was described by the Group Français de Cytogénétique Hématologique in 1986 presenting with classical morphologic and hematologic features and a peripheral blood monocytosis ranging from 1 to 5109/L [6]. If the FAB group criteria are considered, it cannot be said if the two described cases belong to the same subtype because, although the case presented herein is included in the subtype called myeloproliferative-CMMoL with WBC count 13109/L [2], in the first described case by the French group there is no mention of the WBC count. The two reported cases have monosomy 15 in mosaicism, with a less frequent normal clone. Although there are only two described cases of monosomy 15 as a sole anomaly, monosomy 15 in complex karyotypes is a frequent event in myelodysplastic syndrome
(MDS) particularly in refractory anemia with excess of blasts (RAEB). In a review of the literature [5,7] we found 53 cases of MDS presenting monosomy 15 plus other cytogenetic abnormalities. Among them, there were 18 RAEB, 14 refractory anemias with excess of blasts in transformation (RAEB-t), six MDS not otherwise specificated, six refractory anemias, five refractory anemias with ringed sideroblasts and four CMMoL. Regarding monosomy 15 in CMMoL, the characteristics of these four CMMoL cases can be seen in Table 1. The most frequently involved chromosomes accompanying monosomy 15 in these subgroups were chromosomes 5, 7, 17, 12, and 18 (Table 2). Several oncogenes involved in myeloid lineage have been mapped on chromosome 15 such as PML (implicated in t(15;17)(q22;q21) characteristic of acute promyelocytic leukemia) and AF15q14 (involved in t(11;15)(q23;q14) found in acute myeloblastic leukemia with maturation). These genes could be candidate genes involved in the development of leukemia [9]. It is noticeable that trisomy 15, often associated with loss of Y chromosome as an age-related effect, is found in myeloid and lymphoid lineages MDS, acute nonlymphocytic leukemia,
Table 1 Monosomy 15 and CMMoL: Review of reported cases as a sole abnormality or accompanied by other cytogenetic aberrations [5] Monosomy 15 in CMMoL As a sole abnormality With other abnormalities
Authors
Karyotype
GFCH 1986 [6] Present case GFCH 1986 [6] Horike et al. 1994 [7] Collado et al. 1999 [8]
46,XX[3]/45,XX,15[45] 46,XX[5]/46,XX,15[15] 46,XY[2]/45,XX,5,7,t(5;7)(q21;q11),6,15,21,r,2mar[10] 46,XY,der(1;15)t(q?;q?),15[9] 45,X,add(Xq),1,del(5),11,17,add(18q)/ 43,X,Y,2,4,add(4)(q34),7,8,del(11)(q23),13,15,17
Boldface: monoscomy 15. Brackets indicate the number of studied metaphases. Abbreviations: AML, acute myeloblastic leukemia; GFCH, Group Français de Cytogénétique Hématologique.
Survival (months)
Transformation
51 6 1 23 9
AML — — — AML
L. Zamora et al. / Cancer Genetics and Cytogenetics 134 (2002) 165–167 Table 2 The most frequent abnormalities accompanying monosomy 15 and the number of patients affected Chromosome 5
7
12
17
18
Abnormality (the most frequently involved regions)
Number of patients
5 5q[q11q35] others 7 7q[q11q36] others 12 add(12p)[p11p12] others 17 add(17p)[p11p12] others 18 others
22 19 12 19 9 14 4 6 16 11 5 14 15 10
acute lymphocytic leukemia, chronic lymphocytic leukemia but it has been also reported in patients free of hematological malignancies [10,11]. In conclusion, with these data we cannot associate monosomy 15 with a special subtype of CMMoL, but it can be suggested that the mentioned chromosome could be involved in the development of a MDS. Acknowledgments This work has been supported in part by the grant FIS 01/424 from Ministerio de Sanidad y Consumo. The authors wish to thank Rosa Maria Vilà, Rosa Navarro and Maria Carmen Vela for their excellent technical assistance.
167
References [1] Florensa L, Woessner S, Lafuente R, Buxó J, Almarcha J, Marill MR, Sans-Sabrafen J. In vitro granulopoiesis in myelodysplastic syndromes (MDS) according to the FAB classification. In: Schmalzl F, Mufti GJ, editors. Myelodysplastic syndromes. Berlin: Springer, 1996, pp. 222–32. [2] Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick H, Sultan C, Cox C. The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 1994;87:746–54. [3] Vallespí T, Imbert M, Mecucci C, Preudhomme C, Fenaux P. Diagnosis, classification, and cytogenetics of myelodysplastic syndromes (review). Haematologica 1998;83:258–75. [4] ISCN. Guidelines for Cancer Cytogenetics, Supplement to An International System for Human Cytogenetic Nomenclature. Mitelman F, editor. Basel: S. Karger, 1995. [5] Mitelman F, Johansson B, Mertens F (eds.) Mitelman database of chromosome aberrations in cancer. Available at: http//cgap.nci.nih.gov/ Chromosomes/Mitelman. Accessed: September 7, 2001. [6] Group Français de Cytogénétique Hématologique. Cytogenetics of chronic myelomonocytic leukemia. Cancer Genet Cytogenet 1986; 21:11–30. [7] Horike S, Misawa S, Nakai H, Kaneko H, Yokota S, Taniwaki M, Yamane Y, Inazawa J, Abe T, Kashima K. N-ras mutation and karyotypic evolution are closely associated with leukemic transformation in myelodysplastic syndrome. Leukemia 1994;8:1331–6. [8] Collado R, Badia L, Garcia S, Sanchez H, Prieto F, Carbonell F. Chromosome 11 abnormalities in myelodysplastic syndromes. Cancer Genet Cytogenet 1999;114:58–61. [9] Huret, JS. Atlas of genetics and cytogenetics in oncology and haematology. Available at: http://www.infobiogen.fr/services/chromcancer. Accessed: September 17, 2001. [10] Smith A, Watson N, Sharma P. Frequency of trisomy 15 and loss of the Y chromosome in adult leukemia. Cancer Genet Cytogenet 1999; 114:108–11. [11] Sinclair EJ, Potter AM, Watmore AE, Fithcett M, Ross F. Trisomy 15 associated with loss of the Y chromosome in bone marrow: a possible new aging effect. Cancer Genet Cytogenet 1998;105:20–3.