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Chronic myelomonocytic leukemia with t(13;14) in a child
SHORT COMMUNICATIONS Chronic Myelomonocytic Leukemia with t(13;14) in a Child N. Bown, S. M. Yule, J. Evans, J. Kernahan, and M. M. Reid
ABSTRACT: Bone marrow cells from a child with chronic myelomonocytic leukemia showed an acquired, non-Robertsonian translocation between chromosomes 13 and 14, t(13;14)(q12.?2;q32.?3). This rearrangement has not previously been reported in childhood myeloproliferative or myelodysplastic disorders.
INTRODUCTION Chronic myeloproliferative disorders (MPD) or myelodysplastic syndromes (MDS) are rare in childhood, but the range of hematologic and cytogenetic features associated with them is widening [1]. We present a case of chronic myelomonocytic leukemia [CMMoL], indistinguishable in many respects from the disease in adults, associated with a unique clonal cytogenetic abnormality. CASE REPORT
An 8-year-old white boy of first-cousin parents presented with a 6-week history of general lethargy and weight loss. He had widespread lymphadenopathy. His liver was enlarged 4 cm and spleen 8 cm below the costal margins. There was no skin rash or bruising. The blood count showed hemoglobin 9.5 g/dL, MCV 87 fl, white blood cells 32.9 × 109/L, of which 14.8 × 109/L were neutrophils, 9.5 x 109/L lymphocytes, 4.8 x 109/L monocytes, 3.6 × 109/L myelocytes, and platelets 114 x 109/L. No blasts were seen in the peripheral blood. Hypogranular and pseudo-Pelger neutrophils were present. The plasma lysozyme was 950/~g/mL. Fetal hemoglobin was 0.8%. Leucocyte alkaline phosphatase score was 0 (control 126). Bone marrow aspirate showed intensely cellular smears with left shifted myeloid hyperplasia and similar dysplastic changes in neutrophils. Unlike the peripheral blood, monocytes, though present, were not prominent. Blasts accounted for 6% of cells. No Auer rods were seen. Erythropoiesis and megakaryocytes appeared normal. Myeloid ceils were Sudan black B and chloroacetate esterase positive; monocytes were alphanaphthylacetate esterase posiFram the Department of Human Genetics, University of Newcastle u p o n Tyne (N. B., J. E.), a~d Departments of Child Health (S. M. Y., J. K.) a n d Haematology [M. M. R.], Royal Victoria Infirmary, Newcastle u p o n Tyne, United Kingdom. Address r e p r i n t requests to: N. Bown, Department of H u m a n Genetics, 19 Claremont Place, Newcastle upon Tyne, NE2 4AA, UK. Received July 11, 1991; accepted August 21, 1991.
tive. Marrow histology showed 100% cellularity, confirmed the myeloid hyperplasia, and showed moderate widespread reticulin fibrosis. Serologic investigations showed no evidence of recent or continuing Epstein-Barr virus (EBV) infection. Results of cytogenetic investigations are shown below. A diagnosis of CMMoL was made, according to standard FAB criteria. Initial treatment with hydroxyurea resulted in a fall in the total white cell count to 18 x 109/L but monocytosis persisted. Within 1 week of stopping hydroxyurea, liver, spleen, and lymph nodes enlarged massively, he developed marked edema of the face and torso, ascites, and pleural effusions, the white cell count rose to 38 x 109/L, of which 15 x 109/L were monocytes, and it was feared that he would not survive. He was then treated aggressively with the Medical Research Council's AML 10 regimen (details of which are available from the authors). Liver, spleen, and nodes shrank, but remained enlarged. White cells fell to normal, with a normal differential count, and dysplastic neutrophils disappeared. Bone marrow cytology and histology returned to normal. Although complete remission was not achieved, reflected by the persisting organomegaly, he remains alive 4 months after diagnosis, and cytogenetic investigations (see below) have confirmed the impact of this treatment on his bone marrow. In the absence of an HLA-compatible sibling, bone marrow transplant from a matched, unrelated donor is being considered. CYTOGENETIC FINDINGS
Bone marrow at presentation was cultured and harvested according to standard protocols and metaphase preparations G-banded with trypsin and Leishman's stain. An apparently balanced, reciprocal, non-Robertsonian translocation was observed in 102 cells; 46,XY, t(13;14)(q12.?2;q32.?3). An example is shown in Fig. 1. A normal 46,XY karyotype was noted in three cells. Standard PHA-stimulated cultures of peripheral blood showed the translocation in about 50% of metaphase cells. A further PHA-stimulated culture was given over to a routine
190 Cancer Genet Cytogenet 60:190-192 (1992) 0165-4608/92/$05.00
© 1992 Elsevier Science Publishing Co. Inc. 655 Avenue of the Americas, New York, NY 10010
CMML with t(13;14) in a Child
p
q
191
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Figure I Translocation (13;14)(q12.?2;q32.?3) in bone marrow metaphase. Normal homologues are shown on the left, with suggested breakpoints indicated by arrows.
thymidine synchronization technique to produce extended banding. The translocated cell line failed to respond to this procedure, and only 46,XY cells were produced. Because CMMoL is rare in children and this translocation is not a recognized leukemia-associated abnormality, and with the history of consanguinity, the possibility that the translocation represented a constitutional mosaic condition was considered. This was rejected following two further observations: (i) subsequent marrow samples after 7 and 9 weeks showed a change in the ratio of translocated to normal cells from 102:3 to 3:39 and then to 0:100, and (ii) the translocation was not detected in 100 metaphases from a fibroblast culture established from the second marrow sample. DISCUSSION
Traditionally, MPD of childhood have been divided into classical Ph positive chronic granulocytic leukemia (CGL) and juvenile chronic myeloid leukemia (JCML), but it has become clear that this approach is simplistic [1]. Other forms of MPD or MDS, often associated with monosomy 7 or persistent EBV infection, have been described [2, 3]. The leukocytosis in the case described here clearly has a clonal, not reactive, basis. The hematologic and cytogenetic features are not those of CGL. There are few similarities with JCML. In particular, this child is older than the typical case of JCML, there is no skin rash or purpura and only mild thrombocytopenia, and no elevation of fetal hemoglobin. The clinical and hematologic features therefore conform more closely to those of the predominantly adultassociated syndrome of CMMoL.
No chromosome change has been associated specifically with CMMoL, the most frequently reported abnormalities being those generally encountered in other myeloid leukemias. For example, in one large series [4], monosomy 7(-7), trisomy 8(+8), i(17q), and rearrangements of 12p were identified as the most frequent single chromosome changes. In a study of 38 children with sub-acute and chronic myelomonocytic leukemia, most of whom probably had true JCML [5], gain of a C group chromosome, but not monosomy 7, was noted. More recently, rearrangement of band 11p15 has been proposed as a feature of childhood MPD or MDS with hematologic similarities to CGL [6], while a report of subacute myelomonocytic leukemia in monozygotic twins implicated gain of chromosome 13 material in disease progression [7]. To our knowledge, this translocation has not previously been associated with hematologic malignancy. The chromosome 13 breakpoint is within band q12. It is interesting that this is a recognized breakpoint in interstitial deletions of chromosome 13 associated with MPD and MDS [8] and is the site of the oncogene FLT [9]. The chromosome 14 breakpoint appears to be in band q32. Established rearrangements of this region have hitherto been associated with lymphoid malignancy [8]. This case extends our knowledge of the clinical, hematologic, and cytogenetic features of childhood MDS. REFERENCES
1. Chessells JM (1991): Myelodysplasia. Bailliere's Clinical Haematology, 4:459-482. 2. Sieff CA, Chessells JM, Harvey BAM, Pickthall VJ, Lawler SD (1981): Monosomy 7 in childhood: a myeloproliferative disorder. Br J Haematol 49:235-249.
192
3. Stollman B, Fonatsch C, Havers W (1985): Persistent EpsteinBarr virus infection with monosomy 7 or chromosome 3 abnormality in childhood myeloproliferative disorders. Br J Haematol 60:183-186. 4. Groupe Francais de Cytogenetique Hematologique (1986): Cytogenetics of chronic myelomonocytic leukemia. Cancer Genet Cytogenet 21:11-30. 5. Castro-Malaspina H, Schaison G, Passe S, Pasquier A, Berger R, Bayle Weisberger C, Miller D, Seligmann M, Bernard J (1984): Subacute and chronic myelomonocytic leukemia in children (juvenile CML). Cancer 54:675-686.
N. B o w n et al.
6. Inaba T, Hayashi Y, Hanada R, Nakashima M, Yamamoto K, Nishida T (1988): Childhood myelodysplastic syndromes with 11p15 translocation. Cancer Genet Cytogenet 34:41-46. 7. Massaad L, Prieur M, Gaud C, Fischer A, Dutrillaux B (1989): Unusual karyotypic evolution in subacute myelomonocytic leukemia in two monozygotic twins. Cancer Genet Cytogenet 38:205-213. 8. Human Gene Mapping 10.5. Report of the committee on chromosome changes in neoplasia (1990): Cytogenet Cell Genet 55:358-386. 9. Hecht F (1988): Oncogene location update. Cancer Genet Cytogenet 31:142-143.
ABSTRACT: Bone marrow cells from a child with chronic myelomonocytic leukemia showed an acquired, non-Robertsonian translocation between chromosomes 13 and 14, t(13;14)(q12.?2;q32.?3). This rearrangement has not previously been reported in childhood myeloproliferative or myelodysplastic disorders.
INTRODUCTION Chronic myeloproliferative disorders (MPD) or myelodysplastic syndromes (MDS) are rare in childhood, but the range of hematologic and cytogenetic features associated with them is widening [1]. We present a case of chronic myelomonocytic leukemia [CMMoL], indistinguishable in many respects from the disease in adults, associated with a unique clonal cytogenetic abnormality. CASE REPORT
An 8-year-old white boy of first-cousin parents presented with a 6-week history of general lethargy and weight loss. He had widespread lymphadenopathy. His liver was enlarged 4 cm and spleen 8 cm below the costal margins. There was no skin rash or bruising. The blood count showed hemoglobin 9.5 g/dL, MCV 87 fl, white blood cells 32.9 × 109/L, of which 14.8 × 109/L were neutrophils, 9.5 x 109/L lymphocytes, 4.8 x 109/L monocytes, 3.6 × 109/L myelocytes, and platelets 114 x 109/L. No blasts were seen in the peripheral blood. Hypogranular and pseudo-Pelger neutrophils were present. The plasma lysozyme was 950/~g/mL. Fetal hemoglobin was 0.8%. Leucocyte alkaline phosphatase score was 0 (control 126). Bone marrow aspirate showed intensely cellular smears with left shifted myeloid hyperplasia and similar dysplastic changes in neutrophils. Unlike the peripheral blood, monocytes, though present, were not prominent. Blasts accounted for 6% of cells. No Auer rods were seen. Erythropoiesis and megakaryocytes appeared normal. Myeloid ceils were Sudan black B and chloroacetate esterase positive; monocytes were alphanaphthylacetate esterase posiFram the Department of Human Genetics, University of Newcastle u p o n Tyne (N. B., J. E.), a~d Departments of Child Health (S. M. Y., J. K.) a n d Haematology [M. M. R.], Royal Victoria Infirmary, Newcastle u p o n Tyne, United Kingdom. Address r e p r i n t requests to: N. Bown, Department of H u m a n Genetics, 19 Claremont Place, Newcastle upon Tyne, NE2 4AA, UK. Received July 11, 1991; accepted August 21, 1991.
tive. Marrow histology showed 100% cellularity, confirmed the myeloid hyperplasia, and showed moderate widespread reticulin fibrosis. Serologic investigations showed no evidence of recent or continuing Epstein-Barr virus (EBV) infection. Results of cytogenetic investigations are shown below. A diagnosis of CMMoL was made, according to standard FAB criteria. Initial treatment with hydroxyurea resulted in a fall in the total white cell count to 18 x 109/L but monocytosis persisted. Within 1 week of stopping hydroxyurea, liver, spleen, and lymph nodes enlarged massively, he developed marked edema of the face and torso, ascites, and pleural effusions, the white cell count rose to 38 x 109/L, of which 15 x 109/L were monocytes, and it was feared that he would not survive. He was then treated aggressively with the Medical Research Council's AML 10 regimen (details of which are available from the authors). Liver, spleen, and nodes shrank, but remained enlarged. White cells fell to normal, with a normal differential count, and dysplastic neutrophils disappeared. Bone marrow cytology and histology returned to normal. Although complete remission was not achieved, reflected by the persisting organomegaly, he remains alive 4 months after diagnosis, and cytogenetic investigations (see below) have confirmed the impact of this treatment on his bone marrow. In the absence of an HLA-compatible sibling, bone marrow transplant from a matched, unrelated donor is being considered. CYTOGENETIC FINDINGS
Bone marrow at presentation was cultured and harvested according to standard protocols and metaphase preparations G-banded with trypsin and Leishman's stain. An apparently balanced, reciprocal, non-Robertsonian translocation was observed in 102 cells; 46,XY, t(13;14)(q12.?2;q32.?3). An example is shown in Fig. 1. A normal 46,XY karyotype was noted in three cells. Standard PHA-stimulated cultures of peripheral blood showed the translocation in about 50% of metaphase cells. A further PHA-stimulated culture was given over to a routine
190 Cancer Genet Cytogenet 60:190-192 (1992) 0165-4608/92/$05.00
© 1992 Elsevier Science Publishing Co. Inc. 655 Avenue of the Americas, New York, NY 10010
CMML with t(13;14) in a Child
p
q
191
t ~
i2
pl
'.
q z
, I~
iS
der(13)
3 ........a
13
14
i I der(14)
Figure I Translocation (13;14)(q12.?2;q32.?3) in bone marrow metaphase. Normal homologues are shown on the left, with suggested breakpoints indicated by arrows.
thymidine synchronization technique to produce extended banding. The translocated cell line failed to respond to this procedure, and only 46,XY cells were produced. Because CMMoL is rare in children and this translocation is not a recognized leukemia-associated abnormality, and with the history of consanguinity, the possibility that the translocation represented a constitutional mosaic condition was considered. This was rejected following two further observations: (i) subsequent marrow samples after 7 and 9 weeks showed a change in the ratio of translocated to normal cells from 102:3 to 3:39 and then to 0:100, and (ii) the translocation was not detected in 100 metaphases from a fibroblast culture established from the second marrow sample. DISCUSSION
Traditionally, MPD of childhood have been divided into classical Ph positive chronic granulocytic leukemia (CGL) and juvenile chronic myeloid leukemia (JCML), but it has become clear that this approach is simplistic [1]. Other forms of MPD or MDS, often associated with monosomy 7 or persistent EBV infection, have been described [2, 3]. The leukocytosis in the case described here clearly has a clonal, not reactive, basis. The hematologic and cytogenetic features are not those of CGL. There are few similarities with JCML. In particular, this child is older than the typical case of JCML, there is no skin rash or purpura and only mild thrombocytopenia, and no elevation of fetal hemoglobin. The clinical and hematologic features therefore conform more closely to those of the predominantly adultassociated syndrome of CMMoL.
No chromosome change has been associated specifically with CMMoL, the most frequently reported abnormalities being those generally encountered in other myeloid leukemias. For example, in one large series [4], monosomy 7(-7), trisomy 8(+8), i(17q), and rearrangements of 12p were identified as the most frequent single chromosome changes. In a study of 38 children with sub-acute and chronic myelomonocytic leukemia, most of whom probably had true JCML [5], gain of a C group chromosome, but not monosomy 7, was noted. More recently, rearrangement of band 11p15 has been proposed as a feature of childhood MPD or MDS with hematologic similarities to CGL [6], while a report of subacute myelomonocytic leukemia in monozygotic twins implicated gain of chromosome 13 material in disease progression [7]. To our knowledge, this translocation has not previously been associated with hematologic malignancy. The chromosome 13 breakpoint is within band q12. It is interesting that this is a recognized breakpoint in interstitial deletions of chromosome 13 associated with MPD and MDS [8] and is the site of the oncogene FLT [9]. The chromosome 14 breakpoint appears to be in band q32. Established rearrangements of this region have hitherto been associated with lymphoid malignancy [8]. This case extends our knowledge of the clinical, hematologic, and cytogenetic features of childhood MDS. REFERENCES
1. Chessells JM (1991): Myelodysplasia. Bailliere's Clinical Haematology, 4:459-482. 2. Sieff CA, Chessells JM, Harvey BAM, Pickthall VJ, Lawler SD (1981): Monosomy 7 in childhood: a myeloproliferative disorder. Br J Haematol 49:235-249.
192
3. Stollman B, Fonatsch C, Havers W (1985): Persistent EpsteinBarr virus infection with monosomy 7 or chromosome 3 abnormality in childhood myeloproliferative disorders. Br J Haematol 60:183-186. 4. Groupe Francais de Cytogenetique Hematologique (1986): Cytogenetics of chronic myelomonocytic leukemia. Cancer Genet Cytogenet 21:11-30. 5. Castro-Malaspina H, Schaison G, Passe S, Pasquier A, Berger R, Bayle Weisberger C, Miller D, Seligmann M, Bernard J (1984): Subacute and chronic myelomonocytic leukemia in children (juvenile CML). Cancer 54:675-686.
N. B o w n et al.
6. Inaba T, Hayashi Y, Hanada R, Nakashima M, Yamamoto K, Nishida T (1988): Childhood myelodysplastic syndromes with 11p15 translocation. Cancer Genet Cytogenet 34:41-46. 7. Massaad L, Prieur M, Gaud C, Fischer A, Dutrillaux B (1989): Unusual karyotypic evolution in subacute myelomonocytic leukemia in two monozygotic twins. Cancer Genet Cytogenet 38:205-213. 8. Human Gene Mapping 10.5. Report of the committee on chromosome changes in neoplasia (1990): Cytogenet Cell Genet 55:358-386. 9. Hecht F (1988): Oncogene location update. Cancer Genet Cytogenet 31:142-143.