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Trisomy 11 with loss of the Y chromosome and trisomy 13 in a case of de novo acute myeloid leukemia
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Trisomy 11 with Loss of the Y Chromosome and Trisomy 13 in a Case of De Novo Acute Myeloid Leukemia John Meletis, Michalis Samarkos, Danae Abazis, Evi Michali, Stathis Vavourakis, Eleni Plata, John Rombos, Kostas Konstantopoulos, Konstantinos Pangalos, Xenophon Yataganas, and Dimitris Loukopoulos
ABSTRACT:
We report a man with de novo acute myeloid leukemia (M4 of the FAB classification) bearing two abnormal clones in the bone marrow cells. The clones showed trisomy 11 with loss of the Y chromosome and trisomy 13, respectively.
INTRODUCTION Isolated trisomy 11 and trisomy 13 have been reported as nonrandom chromosomal abnormalities in acute myeloid leukemia. Cytogenetically unrelated clones are a rare finding in acute leukemia. We report here a case of a biclonal abnormality in a patient with a de novo myeloid leukemia (M4 of the FAB classifi.cation). The abnormality consisted of trisomy 11 with loss of the Y, and trisomy 13 (46,X, -Y,+11/47,XY,+13). CASE REPORT A 22-year-old man was referred to us for evaluation of anemia, leukocytosis, and thrombocytopenia. One month before his admission he complained of fatigue and anorexia; 20 days later he ‘developed fever up to 39”C, mouth ulcers, and generalized lymphadenopathy. He also had nausea, feeling of epigastric fullness, and discomfort. Apart from some common diseases of childhood, his past medical history was unremarkable. On clinical examination there was marked hepatomegaly and splenomegaly. The liver extended up to the right upper iliac crest, being firm and sensitive on palpation. The spleen was palpable 7 cm below the left costal margin. The cervical, axillary, and inguinal lymph nodes were
From the First Department of Internal Medicine, University of Athens School of Medicine, Laikon General Hospital; and Diagnostic Genetic Center (D. A., K. I?), Athens, Greece. Address reprint requests to: Dr. John Meletis, First Department of Internal Medicine, University of Athens School of Medicine, Laikon Hospital, Athens :I1527, Greece. Received March 21, 1995; accepted June 19, 1995.
Cancer
Genet
0 Elsevier 655 Avenue
Cytogenet
Science
Inc.,
86:65-68
palpable, firm, mobile, and painless. Percussion of the chest revealed dullness over the left lower field; there was absence of tactile fremitus and decreased breath sounds over the same area. On admission, his hematology was: hemoglobin 11.2 g/ dl, WBC 148 X log/L, platelet count 64 X log/L. The white cell differential count was 3% neutrophils, 12% lymphocytes, and 85% blasts. The rest of the routine laboratory tests were within normal limits, with the exception of an extremely elevated serum lactate dehydrogenase (10,000 U/L, normal values < 500 U/L). There was a moderate amount of fluid in the left pleural space in the chest x-ray and massive hepatomegaly and splenomegaly in the CT scan of the abdomen. A bone marrow aspirate showed 90% blasts. The cytochemical examination of the peripheral blood and marrow blasts showed 100% peroxidase and esterase (ANAE) positivity and diffuse PAS positivity with small granules. Immunochemical examination of the peripheral blood and marrow cells revealed the following: CD34(-), CD33 +(50%), CD13 +(80%), CD14 +(45%), CD7(-), CDllc +(40%), CD4 +(45%), CD2(-), CD19 +(8%), CD22 +(lO%), CD61(-), MPO +(97%), Ia +(lOO%), Glyc A(-). According to the morphologic, cytochemical, and immunochemical findings the diagnosis of acute myelogenous leukemia (FAB M4) was made. A chromosomal analysis was performed at this stage. The results are given separately below. He was treated with idarubicin
(1996) 0165-4608/96/$15.00
1996
of the Americas,
12 mg/m’ for
days l-3 and cytarabine 100 mg/m’ in 24-hour infusion for days 1-7. He achieved a complete hematologic remission after the first course and then received the same regimen as consolidation therapy. Subsequently he received four courses of intensified maintenance therapy at 3-wk
:Vew
York,
NY
10010
SSDI
0165-4608(95)00161-H
66
J. Meletis et al.
Figure 1
Karyotype
(RHG banding) with deletion
of chromosome
intervals with high-dose cytarabine, etoposide, plus mitoxantrone, cytarabine plus mitoxantrone, and etoposide plus cytarabine according to the protocol. After completion of maintenance therapy, a bone marrow biopsy and aspirate confirmed the hematologic complete remission; the chromosomal analysis, however, showed minimal residual disease with the same chromosomal abnormalities. CYTOGENETIC
STUDIES
A chromosomal analysis (karyotyping) was carried out on a bone marrow sample at the time of AML diagnosis before any treatment. The RHG banding technique was used and 14 metaphases of bone marrow cells were studied after a Z&hour culture without PHA. Two abnormal clones were observed. The first (70% of the cells) had a trisomy 11 and loss of the Y chromosome. The second one (30% of the cells) had trisomy 13 (Figs. 1 and 2).
Y and trisomy 11 (46, X, -Y, +ll).
DISCUSSION Cytogenetically unrelated clones have been reported in some hematologic malignancies [l]. The combination of trisomy 11 and loss of the Y chromosome with trisomy 13 in a leukemia, to the best of our knowledge, has not been reported thus far. Trisomy 11 has been reported in patients with a de novo AML; as reported, it represents the chromosomal background of translocations involving llq23 band [z]. The underlying molecular event (rearrangement of ALL-l gene) may be more common than the cytogenetic abnormality involving llq23 in de novo AML [3]. Trisomy 11 has been found in combination with other chromosomal abnormalities, namely, trisomy 8, monosomy 7, and loss of the long arm of chromosome 5 (41. Interestingly, it is not common in myelodysplasia. As a part of a combination of more than one malignant clones, it is quite frequent, representing some 25% of the cases [l].
46,X,-Y,+ll
Plus 47,XY,+l3
in De Novo AML
Figure 2
67
Karyotype (RHG banding) with trisomy 13(47,
Trisomy 13 has been. reported as a rare, recurring abnormality in both de novo and secondary leukemia or myelodysplasia-related acute leukemia. This cytogenetic abnormality is believed to be associated with myeloid differentiation of the neoplastic cells and with a differentiation block and morphologic heterogeneity [S). This abnormality also characterizes an undifferentiated phenotype, lineage inconsistency with CD4 and TdT positivity, and in most cases there is a marker of biclonality [6]. As an isolated cytogenetic a?mormality it is believed to have adverse prognostic significance in acute leukemia with low complete remissicln rates and short remission duration and survival [71. Both abnormalities have been found in AML expressing lymphoid markers (CD7, CDZ, CDlO, CD19, CD22, and TdT). Loss of the Y chromosome is not a rare event in acute myeloid leukemia; it is also found in elderly males. Therefore it should not be always considered as a marker of
XY, +13).
malignant clone IS]. The case presented adds this trisomy combination to the nonrandom chromosomal abnormalities found in AML. As this combination (not yet described) seems to be rare, no indication pertaining to its role in the natural course of the disease can be drawn.
REFERENCES T, Morgan R, Sandberg AA (1992): Cytogenetic biclonality in malignant hematologic disorders. Cancer Genet Gytogenet 62:25-28. 2. Schichman SA, Caligiuri MA, Gu Y, Strout MP, Canaani E, 1. Furuya
Bloomfield CD, Croce CM (1994): ALL-l partial duplication acute leukemia. Proc Nat1 Acad Sci USA 91:6236-6239. 3. Caligiuri
in
MA, Schichman SA, Strout MP, Mrozek K, Baer MR, Frankel SR, Barcos M. Herzin GP. Croce CM. Bloomfield CD (1994): Molecular rearrangemvnt of the ALL-l gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocation. Cancer Res ~370-373.
J. Meletis
68 4. Koyabashi H, Kaneko Y, Maseki N, Sakurai M (1990): Karyotypically unrelated clones in acute leukemias and myelodysplastic syndromes. Cancer Genet Cytogenet 47:171-178. 5. Mertens F, Sallerfors B, Heim S, Johansson B, Kristoffersson U, Malm C, Mitelman F (1991): Trisomy 13 as a primary chromosome aberration in acute leukemia. Cancer Genet Cytogenet 56:39-44. 6. Comenzo R, Roth D, Desforges JF, Be&man
EM (1991): Trisomy
13q in a case of acute leukemia with lineage Cancer Genet Cytogenet 55:107-111. 7. Baer R, Bloomfield CD (1992): Leuk Lymphoma 7:1-6.
Trisomy
et
al.
inconsistency.
13 in acute leukemia.
8. United Kingdom Cancer Cytogenetics Group (1992): Loss of the Y chromosome from normal and neoplastic bone marrows. Genes Chromosom Cancer 5:83-86.
Trisomy 11 with Loss of the Y Chromosome and Trisomy 13 in a Case of De Novo Acute Myeloid Leukemia John Meletis, Michalis Samarkos, Danae Abazis, Evi Michali, Stathis Vavourakis, Eleni Plata, John Rombos, Kostas Konstantopoulos, Konstantinos Pangalos, Xenophon Yataganas, and Dimitris Loukopoulos
ABSTRACT:
We report a man with de novo acute myeloid leukemia (M4 of the FAB classification) bearing two abnormal clones in the bone marrow cells. The clones showed trisomy 11 with loss of the Y chromosome and trisomy 13, respectively.
INTRODUCTION Isolated trisomy 11 and trisomy 13 have been reported as nonrandom chromosomal abnormalities in acute myeloid leukemia. Cytogenetically unrelated clones are a rare finding in acute leukemia. We report here a case of a biclonal abnormality in a patient with a de novo myeloid leukemia (M4 of the FAB classifi.cation). The abnormality consisted of trisomy 11 with loss of the Y, and trisomy 13 (46,X, -Y,+11/47,XY,+13). CASE REPORT A 22-year-old man was referred to us for evaluation of anemia, leukocytosis, and thrombocytopenia. One month before his admission he complained of fatigue and anorexia; 20 days later he ‘developed fever up to 39”C, mouth ulcers, and generalized lymphadenopathy. He also had nausea, feeling of epigastric fullness, and discomfort. Apart from some common diseases of childhood, his past medical history was unremarkable. On clinical examination there was marked hepatomegaly and splenomegaly. The liver extended up to the right upper iliac crest, being firm and sensitive on palpation. The spleen was palpable 7 cm below the left costal margin. The cervical, axillary, and inguinal lymph nodes were
From the First Department of Internal Medicine, University of Athens School of Medicine, Laikon General Hospital; and Diagnostic Genetic Center (D. A., K. I?), Athens, Greece. Address reprint requests to: Dr. John Meletis, First Department of Internal Medicine, University of Athens School of Medicine, Laikon Hospital, Athens :I1527, Greece. Received March 21, 1995; accepted June 19, 1995.
Cancer
Genet
0 Elsevier 655 Avenue
Cytogenet
Science
Inc.,
86:65-68
palpable, firm, mobile, and painless. Percussion of the chest revealed dullness over the left lower field; there was absence of tactile fremitus and decreased breath sounds over the same area. On admission, his hematology was: hemoglobin 11.2 g/ dl, WBC 148 X log/L, platelet count 64 X log/L. The white cell differential count was 3% neutrophils, 12% lymphocytes, and 85% blasts. The rest of the routine laboratory tests were within normal limits, with the exception of an extremely elevated serum lactate dehydrogenase (10,000 U/L, normal values < 500 U/L). There was a moderate amount of fluid in the left pleural space in the chest x-ray and massive hepatomegaly and splenomegaly in the CT scan of the abdomen. A bone marrow aspirate showed 90% blasts. The cytochemical examination of the peripheral blood and marrow blasts showed 100% peroxidase and esterase (ANAE) positivity and diffuse PAS positivity with small granules. Immunochemical examination of the peripheral blood and marrow cells revealed the following: CD34(-), CD33 +(50%), CD13 +(80%), CD14 +(45%), CD7(-), CDllc +(40%), CD4 +(45%), CD2(-), CD19 +(8%), CD22 +(lO%), CD61(-), MPO +(97%), Ia +(lOO%), Glyc A(-). According to the morphologic, cytochemical, and immunochemical findings the diagnosis of acute myelogenous leukemia (FAB M4) was made. A chromosomal analysis was performed at this stage. The results are given separately below. He was treated with idarubicin
(1996) 0165-4608/96/$15.00
1996
of the Americas,
12 mg/m’ for
days l-3 and cytarabine 100 mg/m’ in 24-hour infusion for days 1-7. He achieved a complete hematologic remission after the first course and then received the same regimen as consolidation therapy. Subsequently he received four courses of intensified maintenance therapy at 3-wk
:Vew
York,
NY
10010
SSDI
0165-4608(95)00161-H
66
J. Meletis et al.
Figure 1
Karyotype
(RHG banding) with deletion
of chromosome
intervals with high-dose cytarabine, etoposide, plus mitoxantrone, cytarabine plus mitoxantrone, and etoposide plus cytarabine according to the protocol. After completion of maintenance therapy, a bone marrow biopsy and aspirate confirmed the hematologic complete remission; the chromosomal analysis, however, showed minimal residual disease with the same chromosomal abnormalities. CYTOGENETIC
STUDIES
A chromosomal analysis (karyotyping) was carried out on a bone marrow sample at the time of AML diagnosis before any treatment. The RHG banding technique was used and 14 metaphases of bone marrow cells were studied after a Z&hour culture without PHA. Two abnormal clones were observed. The first (70% of the cells) had a trisomy 11 and loss of the Y chromosome. The second one (30% of the cells) had trisomy 13 (Figs. 1 and 2).
Y and trisomy 11 (46, X, -Y, +ll).
DISCUSSION Cytogenetically unrelated clones have been reported in some hematologic malignancies [l]. The combination of trisomy 11 and loss of the Y chromosome with trisomy 13 in a leukemia, to the best of our knowledge, has not been reported thus far. Trisomy 11 has been reported in patients with a de novo AML; as reported, it represents the chromosomal background of translocations involving llq23 band [z]. The underlying molecular event (rearrangement of ALL-l gene) may be more common than the cytogenetic abnormality involving llq23 in de novo AML [3]. Trisomy 11 has been found in combination with other chromosomal abnormalities, namely, trisomy 8, monosomy 7, and loss of the long arm of chromosome 5 (41. Interestingly, it is not common in myelodysplasia. As a part of a combination of more than one malignant clones, it is quite frequent, representing some 25% of the cases [l].
46,X,-Y,+ll
Plus 47,XY,+l3
in De Novo AML
Figure 2
67
Karyotype (RHG banding) with trisomy 13(47,
Trisomy 13 has been. reported as a rare, recurring abnormality in both de novo and secondary leukemia or myelodysplasia-related acute leukemia. This cytogenetic abnormality is believed to be associated with myeloid differentiation of the neoplastic cells and with a differentiation block and morphologic heterogeneity [S). This abnormality also characterizes an undifferentiated phenotype, lineage inconsistency with CD4 and TdT positivity, and in most cases there is a marker of biclonality [6]. As an isolated cytogenetic a?mormality it is believed to have adverse prognostic significance in acute leukemia with low complete remissicln rates and short remission duration and survival [71. Both abnormalities have been found in AML expressing lymphoid markers (CD7, CDZ, CDlO, CD19, CD22, and TdT). Loss of the Y chromosome is not a rare event in acute myeloid leukemia; it is also found in elderly males. Therefore it should not be always considered as a marker of
XY, +13).
malignant clone IS]. The case presented adds this trisomy combination to the nonrandom chromosomal abnormalities found in AML. As this combination (not yet described) seems to be rare, no indication pertaining to its role in the natural course of the disease can be drawn.
REFERENCES T, Morgan R, Sandberg AA (1992): Cytogenetic biclonality in malignant hematologic disorders. Cancer Genet Gytogenet 62:25-28. 2. Schichman SA, Caligiuri MA, Gu Y, Strout MP, Canaani E, 1. Furuya
Bloomfield CD, Croce CM (1994): ALL-l partial duplication acute leukemia. Proc Nat1 Acad Sci USA 91:6236-6239. 3. Caligiuri
in
MA, Schichman SA, Strout MP, Mrozek K, Baer MR, Frankel SR, Barcos M. Herzin GP. Croce CM. Bloomfield CD (1994): Molecular rearrangemvnt of the ALL-l gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocation. Cancer Res ~370-373.
J. Meletis
68 4. Koyabashi H, Kaneko Y, Maseki N, Sakurai M (1990): Karyotypically unrelated clones in acute leukemias and myelodysplastic syndromes. Cancer Genet Cytogenet 47:171-178. 5. Mertens F, Sallerfors B, Heim S, Johansson B, Kristoffersson U, Malm C, Mitelman F (1991): Trisomy 13 as a primary chromosome aberration in acute leukemia. Cancer Genet Cytogenet 56:39-44. 6. Comenzo R, Roth D, Desforges JF, Be&man
EM (1991): Trisomy
13q in a case of acute leukemia with lineage Cancer Genet Cytogenet 55:107-111. 7. Baer R, Bloomfield CD (1992): Leuk Lymphoma 7:1-6.
Trisomy
et
al.
inconsistency.
13 in acute leukemia.
8. United Kingdom Cancer Cytogenetics Group (1992): Loss of the Y chromosome from normal and neoplastic bone marrows. Genes Chromosom Cancer 5:83-86.