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A Novel Dicentric Deleted Chromosome 21 Arising from Tandem Translocation
A Novel Dicentric Deleted Chromosome 21 Arising from Tandem Translocation L. Robinson, L. Robson, P. Sharma, N. Watson, M. Hertzberg, and A. Smith
ABSTRACT: We present a 26-year-old patient with myelodysplastic syndrome (MDS). Initial bone marrow cytogenetics with G-banding showed a rearranged chromosome 21, which was dicentric and bisatellited on CBG- and NOR-banding. Fluorescence in situ hybridization helped to characterize the structure, using a whole chromosome 21 paint and the locus specific AML1 gene probe. The rearranged 21 consisted solely of chromosome 21 material, contained only one copy of AML1, and was not a trisomy, but a deleted tandem translocation. The MDS transformed to acute myeloid leukemia (AML), and the patient died almost 12 months post-diagnosis. Cytogenetics was performed three times during the course of the disease, and the dicentric chromosome 21 was present throughout. Although there are a number of published rearrangements of chromosome 21 in MDS and AML, most are isodicentrics. We could not find another case of an abnormal chromosome 21 with the same structure as reported here. © 2000 Elsevier Science Inc. All rights reserved.
INTRODUCTION Myelodysplastic syndromes (MDSs) are a heterogenous group of marrow disorders characterized by bone marrow dysfunction due to defective hemopoietic cells and progressive peripheral blood cytopenias [1–3]. Myelodysplastic syndrome frequently transforms to acute myeloid leukemia (AML), and chromosomal abnormalities in MDS are nonrandom and overlap with AML. The most common include monosomy 5,del(5q), monosomy 7, del(7q), trisomy (8), del(20q), and ⫺Y, [1, 3, 4]. Abnormalities of chromosome 21 have mainly involved acquired trisomy 21, reported in both MDS and AML; however, estimates of the occurrence of trisomy 21 varies from infrequent [1], to 5% of cases of AML [5–7]. The clinical and prognostic significance of acquired trisomy 21 in MDS or AML is not known [8, 9]; as in ⵑ90% of these cases, the trisomy 21 is part of a complex karyotype [5]. Few cases of structural rearrangements of chromosome 21 in MDS and AML have ben reported [9–11]. Isodicentric rearrangements comprise the bulk of struc-
From the Department of Cytogenetics (L. R., L. R., P. S., N. W., A. S.), Royal Alexandra Hospital for Children, Parramatta, Australia; and the Department of Haematology (M. H.), Westmead Hospital, Parramatta, Australia. Address reprint requests to: Dr. A. Smith, Department of Cytogenetics, Royal Alexandra Hospital for Children, P.O. Box 3515, Parramatta, NSW 2124, Australia. Received December 10, 1999; accepted February 24, 2000. Cancer Genet Cytogenet 121:208–211 (2000) 2000 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
tural abnormality [9, 11], occasionally with the der(21) in additional aneuploidy, leading to trisomy or tetrasomy for the expression of genes on 21q. The breakpoints were frequently at 21q22, which overlaps with the myeloid translocations t(3;21), t(8;21), and (16;21) [1] and also the lymphoid translocation t(12;21) [12, 13]. The 21q22 locus has been linked to the pathogenesis of AML and acute lymphoblastic leukemia (ALL) through the rearrangement of the gene CBFA2 (also known as AML1) in the translocations t(8;21), t(3;21), and t(12;21) [12], although not in t(16;21) [13]. We present a patient with MDS transforming to AML, with a novel rearrangement of chromosome 21 characterized by cytogenetic banding techniques and fluorescence in situ hybridization (FISH). CASE HISTORY A 26-year-old female presented with macrocytic anemia. Blood tests revealed a white cell count of 5.3 ⫻ 109/L, red cell count of 3.8 ⫻ 1012/L, platelet count of 248 ⫻ 109/L, and hemoglobin value of 110 g/L. The bone marrow aspirate showed extensive replacement of fat and normal hemopoietic elements by blast cells. There were few megakaryocyte and erythroid cells. The diagnosis was MDS RAEB. The blood film changed 8 months post-diagnosis, with evidence of transformation to AML (90% blasts). The patient commenced combination chemotherapy with flu-
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Novel dic (21) darabine and high-dose cytarabine and G-CSF (FLAG regimen); however she died 2 months later. METHODS Cytogenetics/FISH Chromosome analysis and karyotyping were performed by standard techniques previously described [14] on bone marrow aspirates taken at diagnosis, and 8 months and 10 months post-diagnosis. In addition to GTG-banding, CBGand NOR-banding were performed on the diagnostic sample. Fluorescence in situ hybridization was performed on two separate occasions on slides prepared from the cell suspension stored from the diagnostic bone marrow specimen following methods previously described [13]. Initially, a whole chromosome 21 paint was used (-wcp21q; Vysis, directly labeled with SpectrumOrange, red paint). The second hybridization used a locus specific gene probe, AML1 (Vysis, directly labeled with SpectrumOrange, red signal) localized to 21q22.3 [15]. RESULTS The cytogenetic findings are presented in Table 1 and Figures 1 and 2. No normal cells were seen on cytogenetics. With GTG-banding, the patient showed a rearrangement of chromosome 21, along with other structural and numerical rearrangements of various chromosomes. CBG- and NOR-banding showed that the abnormal 21 was dicentric and bisatellited, retaining an “internal” NOR (Fig. 1). The FISH results with the wcp21 probe showed dic(21;21) reported on cytogenetics to be fully painted (n ⫽ 56) (Fig. 3). A single cell was observed with 2 normal chromosome 21 homologues painted (not shown). The FISH with AML1 showed a single distal signal on the unsatellited end of the chromosome in 23 cells (Fig. 3). The signal on FISH (Fig. 3) is deceptively large for a single-copy subtelomeric gene, due to probe enhancement for ease of analysis and in the capturing and image presentation. A normal pattern was seen in two cells (not shown). Thus, while no normal cells were seen on cytogenetics, FISH detected three normal cells (i.e., cells not just part of the abnormal clone, lacking the der[21]).
Table 1 Cytogenetic results Test
No. cells analyzed
Diagnostic
18
8 months PD
12
10 months PD
12
Karyotype 46,XX,del(7)(q22q36)[1]/45,idem, 21,dic(21;21)(p11.2;q22)[17] 45,XX,del(7)(q22q36),⫺21, dic(21;21)(p11.2;q22)[12] 43ⵑ44,XX,⫺7,del(7)(q22q36),⫺9, ⫺11,add(13)(q34),⫺16,del(17) (p11.2),⫺21,dic(21;21)(p11.2;q22), ⫹mar1,⫹mar2[cp12]
Abbreviation: PD, post-diagnosis.
Figure 1 Cytogenetic images of the abnormal chromosome 21 from the diagnostic bone marrow sample. (a) GTG-banding, (b) NOR staining, (c) CBG-banding, (d) an ideogram of the structure of the dic(21;21) based on these techniques.
Interpretation of Abnormal Chromosome 21 The three normal cells established that the structural abnormality of chromosome 21 was not constitutional. Cytogenetics confirmed that the abnormal chromosome 21 was dicentric and bisatellited. The FISH confirmed that the whole chromosome was of chromosome 21 origin and that only one copy of AML1 was present. The structure was a tandem translocation of chromosome 21 with the breakpoint on 21q22 proximal to the AML1 gene, with the deletion of this locus. Thus, overall, there was monosomy 21 for band q22.3. This unbalanced rearrangement appeared to be stable, as it was present on each of three occasions (Table 1). DISCUSSION We describe a novel chromosome 21 rearrangement. Other reports of rearrangements of chromosome 21 in MDS/ Figure 2 Fluorescence in situ hybridization images of the dic(21;21) chromosome (a) Computer inverted image of DAPI staining (done simultaneously with wcp21q), (b) actual DAPI staining from (a), (c) wcp21q (red) showing the entire chromosome painted, (d) AML1 (red) showing a single distal signal.
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Figure 3 The GTG-banded karyotype at 10 months post-diagnosis. The abnormalities are marked by arrows. mar, marker chromosome.
AML include idic(21) or dic(21), not novel in structure per se, but in the number of copies of the structurally rearranged chromosome 21 present [6, 9, 10, 11]. In one report, there were multiple rearrangements of chromosome 21, with not only the dicentric isochromosome, but an add(21q) and a dic(21;22) translocation [11]. In two other reports, a structural abnormality of chromosome 21 was detected in a child with ALL, a marker (21) [16] and a tandem quadruplication [17]. In our case, there were no additional copies of the dic(21;21) and it appeared to be stable throughout the disease. Few other cases have been evaluated with FISH, one examined the structure of abnormal chromosomes 21 with FISH using probe wcp21 (the same used here) and a 21 centromere probe [11], but not a locus specific probe, such as AML1, which we used. Acquired trisomy 21 in myeloid disease [5, 6, 7, 18] implicates involvement of gene(s) on 21q which, when overexpressing, may be a causal factor in the development of AML [5], as has also been suggested for ALL [19]. Our patient did not have trisomy 21, but had a structurally abnormal 21, with the net effect of deletion of the AML1 gene. Thus, our case shows that the relationship between dosage of gene(s) on chromosome 21q with the development or transformation of MDS/AML is not straightfor-
ward and raises the issue of the possible influence of lack of AML1, altering the relative proportions of the various gene products. Other factors that could influence outcome, apart from AML1 loss or disruption, are the fusion gene products, with ETO/AML1 in t(8;21), EAP/AML1 in t(3;21), TEL/AML1 in t(12;21), and FUS/ERG in t(16;21) [12, 13]. These cytogenetically visible rearrangements share the same 21q22 breakpoint; therefore, additional DNA and/or FISH is mandatory to fully characterize complex cases [5, 10], and accurate elucidation of an abnormality is essential to make clinical correlations. However, individual abnormalities within a complex karyotype remain difficult to interpret and the presence of other abnormalities may dictate the clinical outcome (e.g., the ⫺7 in our case) rather than the presence or absence of fusion gene products associated with the abnormal chromosome 21 solely [5].
REFERENCES 1. Heim S, Mitelman F (1995): Acute Myeloid Leukemia. In: Cancer Cytogenetics. Chromosomal and Molecular Genetic Aberrations of Tumor Cells; 2nd Ed. S Heim, F Mitelman, eds. Wiley-Liss, New York. pp. 69–140.
211
Novel dic (21) 2. Fenaux P (1996): Myelodysplastic syndromes. Hematol Cell Ther 38:363–380. 3. Greenberg P, Cox C, Le Beau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997): International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088. 4. Nevill TJ, Fung HC, Shepherd JD, Horsman DE, Nantel SH, Klingermann H-G, Forrest DL, Toze CL, Sutherland HJ, Hogge DE, Nairnan SC, Le A, Brockington DA, Barnett MJ (1998): Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allgeneic bone marrow transplantation. Blood 92:1910–1917.
11.
12.
13.
5. Cortes JE, Kantarjian H, O’Brien S, Keating M, Pierce S, Freireich EJ, Estey (1995): Clinical and prognostic significance of trisomy 21 in adult patients with acute myelogenous leukemia and myelodysplastic syndromes. Leukemia 9:115–117.
14.
6. Furuya T, Morgan R, Sandberg AA (1992): Cytogenetic biclonality in malignant hematologic disorders. Cancer Genet Cytogenet 62:25–28.
15.
7. Dewald GW, Diez-Martin JL, Steffen SL, Jenkins RB, Stupca PJ, Burgert EO (1990): Hematologic disorders in 13 patients with acquired trisomy 21 and 13 individuals with Down syndrome. Am J Med Genet 7:247–250. 8. Wei CH, Yu IT, Tzeng CH, Fan FS, Hsieh RK, Chiou TJ, Liu JH, Chen PM (1996): Trisomy 21 in acute myeloid leukemia. Cancer Genet Cytogenet 86:177–180. 9. Slavc I, Urban C, Haas OA, Kroisel PM, Koller U (1991): Acute megakaryocytic leukemia in children. Clinical, immunologic, and cytogenetic findings in two patients. Cancer 68:2266–2272. 10. Touw I, Donath J, Pouwels K, van Buitenen C, Schipper P, Santini V, Hagemeijer A, Lowenberg B, Delwel R (1991): Acute myeloid leukemias with chromosomal abnormalities
16.
17.
18.
19.
involving the 21q22 region identified by their in vitro responsiveness to interleukin-5. Leukemia 5:687–692. Sankar M, Tanaka K, Arif M, Shintani T, Kumaravel TS, Kyo T, Dohy H, Kamada N (1998): Isodicentric chromosome 21: a novel aberration in acute myeloid leukemia. Cancer Genet Cytogenet 107:69–72. Legare RD, Lu D, Gallagher M, Ho C, Tan X, Barker G, Shimizu K, Ohki M, Lenny N, Hiebert S, Gilliland DG (1997): CBFA2, frequently rearranged in leukemia, is not responsible for a familial leukemia syndrome. Leukemia 11:2111–2119. Sharma P, Watson N, Robson L, Gallo J, Smith A (1999): Novel chromosome 16 abnormality–der(16)del(16) q13t(16;21)(p11.2;q22)–associated with acute myeloid leukemia. Cancer Genet Cytogenet 113:25–28. Flaherty L, Jarvis A, Harris M, Tyrrell V, Smith A (1998): A case of chronic myelomonocytic leukemia with isochromosome 14q: twelve months follow up. Cancer Genet Cytogenet 101:134–137. Avramopoulos D, Cox T, Blaschak JE, Chakravarti A, Antonarakis SE (1992): Linkage mapping of the AML1 gene on human chromosome 21 using a DNAS polymorphism in the 3⬘ untranslated region. Genomics 14:506–507. Le Coniat M, Romana SP, Berger R (1995): Partial chromosome 21 amplification in a child with acute lymphoblastic leukemia. Genes Chromosom Cancer 14:204–209. Baialardo EM, Felice MS, Rossi J, Barreiro C, Gallego MS (1996): Tandem triplication and quadruplication of chromosome 21 in childhood acute lymphoblastic leukemia. Cancer Genet Cytogenet 92:43–45. Kwong YL, Chan LC (1992): Concomitant presence of trisomy 21 and del(9q) in acute myeloid leukemia. Cancer Genet Cytogenet 64:92–94. Berger R (1997): Acute lymphoblastic leukemia and chromosome 21. Cancer Genet Cytogenet 94:8–12.
ABSTRACT: We present a 26-year-old patient with myelodysplastic syndrome (MDS). Initial bone marrow cytogenetics with G-banding showed a rearranged chromosome 21, which was dicentric and bisatellited on CBG- and NOR-banding. Fluorescence in situ hybridization helped to characterize the structure, using a whole chromosome 21 paint and the locus specific AML1 gene probe. The rearranged 21 consisted solely of chromosome 21 material, contained only one copy of AML1, and was not a trisomy, but a deleted tandem translocation. The MDS transformed to acute myeloid leukemia (AML), and the patient died almost 12 months post-diagnosis. Cytogenetics was performed three times during the course of the disease, and the dicentric chromosome 21 was present throughout. Although there are a number of published rearrangements of chromosome 21 in MDS and AML, most are isodicentrics. We could not find another case of an abnormal chromosome 21 with the same structure as reported here. © 2000 Elsevier Science Inc. All rights reserved.
INTRODUCTION Myelodysplastic syndromes (MDSs) are a heterogenous group of marrow disorders characterized by bone marrow dysfunction due to defective hemopoietic cells and progressive peripheral blood cytopenias [1–3]. Myelodysplastic syndrome frequently transforms to acute myeloid leukemia (AML), and chromosomal abnormalities in MDS are nonrandom and overlap with AML. The most common include monosomy 5,del(5q), monosomy 7, del(7q), trisomy (8), del(20q), and ⫺Y, [1, 3, 4]. Abnormalities of chromosome 21 have mainly involved acquired trisomy 21, reported in both MDS and AML; however, estimates of the occurrence of trisomy 21 varies from infrequent [1], to 5% of cases of AML [5–7]. The clinical and prognostic significance of acquired trisomy 21 in MDS or AML is not known [8, 9]; as in ⵑ90% of these cases, the trisomy 21 is part of a complex karyotype [5]. Few cases of structural rearrangements of chromosome 21 in MDS and AML have ben reported [9–11]. Isodicentric rearrangements comprise the bulk of struc-
From the Department of Cytogenetics (L. R., L. R., P. S., N. W., A. S.), Royal Alexandra Hospital for Children, Parramatta, Australia; and the Department of Haematology (M. H.), Westmead Hospital, Parramatta, Australia. Address reprint requests to: Dr. A. Smith, Department of Cytogenetics, Royal Alexandra Hospital for Children, P.O. Box 3515, Parramatta, NSW 2124, Australia. Received December 10, 1999; accepted February 24, 2000. Cancer Genet Cytogenet 121:208–211 (2000) 2000 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
tural abnormality [9, 11], occasionally with the der(21) in additional aneuploidy, leading to trisomy or tetrasomy for the expression of genes on 21q. The breakpoints were frequently at 21q22, which overlaps with the myeloid translocations t(3;21), t(8;21), and (16;21) [1] and also the lymphoid translocation t(12;21) [12, 13]. The 21q22 locus has been linked to the pathogenesis of AML and acute lymphoblastic leukemia (ALL) through the rearrangement of the gene CBFA2 (also known as AML1) in the translocations t(8;21), t(3;21), and t(12;21) [12], although not in t(16;21) [13]. We present a patient with MDS transforming to AML, with a novel rearrangement of chromosome 21 characterized by cytogenetic banding techniques and fluorescence in situ hybridization (FISH). CASE HISTORY A 26-year-old female presented with macrocytic anemia. Blood tests revealed a white cell count of 5.3 ⫻ 109/L, red cell count of 3.8 ⫻ 1012/L, platelet count of 248 ⫻ 109/L, and hemoglobin value of 110 g/L. The bone marrow aspirate showed extensive replacement of fat and normal hemopoietic elements by blast cells. There were few megakaryocyte and erythroid cells. The diagnosis was MDS RAEB. The blood film changed 8 months post-diagnosis, with evidence of transformation to AML (90% blasts). The patient commenced combination chemotherapy with flu-
0165-4608/00/$–see front matter PII S0165-4608(00)00247-8
209
Novel dic (21) darabine and high-dose cytarabine and G-CSF (FLAG regimen); however she died 2 months later. METHODS Cytogenetics/FISH Chromosome analysis and karyotyping were performed by standard techniques previously described [14] on bone marrow aspirates taken at diagnosis, and 8 months and 10 months post-diagnosis. In addition to GTG-banding, CBGand NOR-banding were performed on the diagnostic sample. Fluorescence in situ hybridization was performed on two separate occasions on slides prepared from the cell suspension stored from the diagnostic bone marrow specimen following methods previously described [13]. Initially, a whole chromosome 21 paint was used (-wcp21q; Vysis, directly labeled with SpectrumOrange, red paint). The second hybridization used a locus specific gene probe, AML1 (Vysis, directly labeled with SpectrumOrange, red signal) localized to 21q22.3 [15]. RESULTS The cytogenetic findings are presented in Table 1 and Figures 1 and 2. No normal cells were seen on cytogenetics. With GTG-banding, the patient showed a rearrangement of chromosome 21, along with other structural and numerical rearrangements of various chromosomes. CBG- and NOR-banding showed that the abnormal 21 was dicentric and bisatellited, retaining an “internal” NOR (Fig. 1). The FISH results with the wcp21 probe showed dic(21;21) reported on cytogenetics to be fully painted (n ⫽ 56) (Fig. 3). A single cell was observed with 2 normal chromosome 21 homologues painted (not shown). The FISH with AML1 showed a single distal signal on the unsatellited end of the chromosome in 23 cells (Fig. 3). The signal on FISH (Fig. 3) is deceptively large for a single-copy subtelomeric gene, due to probe enhancement for ease of analysis and in the capturing and image presentation. A normal pattern was seen in two cells (not shown). Thus, while no normal cells were seen on cytogenetics, FISH detected three normal cells (i.e., cells not just part of the abnormal clone, lacking the der[21]).
Table 1 Cytogenetic results Test
No. cells analyzed
Diagnostic
18
8 months PD
12
10 months PD
12
Karyotype 46,XX,del(7)(q22q36)[1]/45,idem, 21,dic(21;21)(p11.2;q22)[17] 45,XX,del(7)(q22q36),⫺21, dic(21;21)(p11.2;q22)[12] 43ⵑ44,XX,⫺7,del(7)(q22q36),⫺9, ⫺11,add(13)(q34),⫺16,del(17) (p11.2),⫺21,dic(21;21)(p11.2;q22), ⫹mar1,⫹mar2[cp12]
Abbreviation: PD, post-diagnosis.
Figure 1 Cytogenetic images of the abnormal chromosome 21 from the diagnostic bone marrow sample. (a) GTG-banding, (b) NOR staining, (c) CBG-banding, (d) an ideogram of the structure of the dic(21;21) based on these techniques.
Interpretation of Abnormal Chromosome 21 The three normal cells established that the structural abnormality of chromosome 21 was not constitutional. Cytogenetics confirmed that the abnormal chromosome 21 was dicentric and bisatellited. The FISH confirmed that the whole chromosome was of chromosome 21 origin and that only one copy of AML1 was present. The structure was a tandem translocation of chromosome 21 with the breakpoint on 21q22 proximal to the AML1 gene, with the deletion of this locus. Thus, overall, there was monosomy 21 for band q22.3. This unbalanced rearrangement appeared to be stable, as it was present on each of three occasions (Table 1). DISCUSSION We describe a novel chromosome 21 rearrangement. Other reports of rearrangements of chromosome 21 in MDS/ Figure 2 Fluorescence in situ hybridization images of the dic(21;21) chromosome (a) Computer inverted image of DAPI staining (done simultaneously with wcp21q), (b) actual DAPI staining from (a), (c) wcp21q (red) showing the entire chromosome painted, (d) AML1 (red) showing a single distal signal.
210
L. Robinson et al.
Figure 3 The GTG-banded karyotype at 10 months post-diagnosis. The abnormalities are marked by arrows. mar, marker chromosome.
AML include idic(21) or dic(21), not novel in structure per se, but in the number of copies of the structurally rearranged chromosome 21 present [6, 9, 10, 11]. In one report, there were multiple rearrangements of chromosome 21, with not only the dicentric isochromosome, but an add(21q) and a dic(21;22) translocation [11]. In two other reports, a structural abnormality of chromosome 21 was detected in a child with ALL, a marker (21) [16] and a tandem quadruplication [17]. In our case, there were no additional copies of the dic(21;21) and it appeared to be stable throughout the disease. Few other cases have been evaluated with FISH, one examined the structure of abnormal chromosomes 21 with FISH using probe wcp21 (the same used here) and a 21 centromere probe [11], but not a locus specific probe, such as AML1, which we used. Acquired trisomy 21 in myeloid disease [5, 6, 7, 18] implicates involvement of gene(s) on 21q which, when overexpressing, may be a causal factor in the development of AML [5], as has also been suggested for ALL [19]. Our patient did not have trisomy 21, but had a structurally abnormal 21, with the net effect of deletion of the AML1 gene. Thus, our case shows that the relationship between dosage of gene(s) on chromosome 21q with the development or transformation of MDS/AML is not straightfor-
ward and raises the issue of the possible influence of lack of AML1, altering the relative proportions of the various gene products. Other factors that could influence outcome, apart from AML1 loss or disruption, are the fusion gene products, with ETO/AML1 in t(8;21), EAP/AML1 in t(3;21), TEL/AML1 in t(12;21), and FUS/ERG in t(16;21) [12, 13]. These cytogenetically visible rearrangements share the same 21q22 breakpoint; therefore, additional DNA and/or FISH is mandatory to fully characterize complex cases [5, 10], and accurate elucidation of an abnormality is essential to make clinical correlations. However, individual abnormalities within a complex karyotype remain difficult to interpret and the presence of other abnormalities may dictate the clinical outcome (e.g., the ⫺7 in our case) rather than the presence or absence of fusion gene products associated with the abnormal chromosome 21 solely [5].
REFERENCES 1. Heim S, Mitelman F (1995): Acute Myeloid Leukemia. In: Cancer Cytogenetics. Chromosomal and Molecular Genetic Aberrations of Tumor Cells; 2nd Ed. S Heim, F Mitelman, eds. Wiley-Liss, New York. pp. 69–140.
211
Novel dic (21) 2. Fenaux P (1996): Myelodysplastic syndromes. Hematol Cell Ther 38:363–380. 3. Greenberg P, Cox C, Le Beau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997): International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088. 4. Nevill TJ, Fung HC, Shepherd JD, Horsman DE, Nantel SH, Klingermann H-G, Forrest DL, Toze CL, Sutherland HJ, Hogge DE, Nairnan SC, Le A, Brockington DA, Barnett MJ (1998): Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allgeneic bone marrow transplantation. Blood 92:1910–1917.
11.
12.
13.
5. Cortes JE, Kantarjian H, O’Brien S, Keating M, Pierce S, Freireich EJ, Estey (1995): Clinical and prognostic significance of trisomy 21 in adult patients with acute myelogenous leukemia and myelodysplastic syndromes. Leukemia 9:115–117.
14.
6. Furuya T, Morgan R, Sandberg AA (1992): Cytogenetic biclonality in malignant hematologic disorders. Cancer Genet Cytogenet 62:25–28.
15.
7. Dewald GW, Diez-Martin JL, Steffen SL, Jenkins RB, Stupca PJ, Burgert EO (1990): Hematologic disorders in 13 patients with acquired trisomy 21 and 13 individuals with Down syndrome. Am J Med Genet 7:247–250. 8. Wei CH, Yu IT, Tzeng CH, Fan FS, Hsieh RK, Chiou TJ, Liu JH, Chen PM (1996): Trisomy 21 in acute myeloid leukemia. Cancer Genet Cytogenet 86:177–180. 9. Slavc I, Urban C, Haas OA, Kroisel PM, Koller U (1991): Acute megakaryocytic leukemia in children. Clinical, immunologic, and cytogenetic findings in two patients. Cancer 68:2266–2272. 10. Touw I, Donath J, Pouwels K, van Buitenen C, Schipper P, Santini V, Hagemeijer A, Lowenberg B, Delwel R (1991): Acute myeloid leukemias with chromosomal abnormalities
16.
17.
18.
19.
involving the 21q22 region identified by their in vitro responsiveness to interleukin-5. Leukemia 5:687–692. Sankar M, Tanaka K, Arif M, Shintani T, Kumaravel TS, Kyo T, Dohy H, Kamada N (1998): Isodicentric chromosome 21: a novel aberration in acute myeloid leukemia. Cancer Genet Cytogenet 107:69–72. Legare RD, Lu D, Gallagher M, Ho C, Tan X, Barker G, Shimizu K, Ohki M, Lenny N, Hiebert S, Gilliland DG (1997): CBFA2, frequently rearranged in leukemia, is not responsible for a familial leukemia syndrome. Leukemia 11:2111–2119. Sharma P, Watson N, Robson L, Gallo J, Smith A (1999): Novel chromosome 16 abnormality–der(16)del(16) q13t(16;21)(p11.2;q22)–associated with acute myeloid leukemia. Cancer Genet Cytogenet 113:25–28. Flaherty L, Jarvis A, Harris M, Tyrrell V, Smith A (1998): A case of chronic myelomonocytic leukemia with isochromosome 14q: twelve months follow up. Cancer Genet Cytogenet 101:134–137. Avramopoulos D, Cox T, Blaschak JE, Chakravarti A, Antonarakis SE (1992): Linkage mapping of the AML1 gene on human chromosome 21 using a DNAS polymorphism in the 3⬘ untranslated region. Genomics 14:506–507. Le Coniat M, Romana SP, Berger R (1995): Partial chromosome 21 amplification in a child with acute lymphoblastic leukemia. Genes Chromosom Cancer 14:204–209. Baialardo EM, Felice MS, Rossi J, Barreiro C, Gallego MS (1996): Tandem triplication and quadruplication of chromosome 21 in childhood acute lymphoblastic leukemia. Cancer Genet Cytogenet 92:43–45. Kwong YL, Chan LC (1992): Concomitant presence of trisomy 21 and del(9q) in acute myeloid leukemia. Cancer Genet Cytogenet 64:92–94. Berger R (1997): Acute lymphoblastic leukemia and chromosome 21. Cancer Genet Cytogenet 94:8–12.