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Amplification of AML1 on a Duplicated Chromosome 21 in Acute Leukemia (2003) 17, 547–553 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases L Harewood1,4, H Robinson1, R Harris1, M Jabbar Al-Obaidi1, GR Jalali1, M Martineau1, AV Moorman1, N Sumption1, S Richards2, C Mitchell3 and CJ Harrison1on behalf of the Medical Research Council Childhood and Adult Leukaemia Working Parties 1Leukaemia Research Fund Cytogenetics Group, Cancer Sciences Division, University of Southampton, Southampton, UK; 2Clinical Trial Service Unit, Radcliffe Infirmary, Oxford, UK; and 3Paediatric Oncology, John Radcliffe Hospital, Oxford, UK This study identifies multiple copies of the AML1 gene on a deletions of AML123,24 have also been reported in myeloid duplicated chromosome 21, dup(21), as a recurrent abnormality disorders. Collectively, these observations point to possible in acute lymphoblastic leukemia (ALL). Clusters of AML1 signals were visible at interphase by fluorescence in situ dosage effects of AML1 in the pathogenesis of leukemia. Further hybridization (FISH). In metaphase, they appeared tandemly studies in larger groups of patients are needed in order to duplicated on marker chromosomes of five distinct morpholo- elucidate the role of AML1 and to help identify the specific gical types: large or small acrocentrics, metacentrics, submeta- chromosomal regions and interacting genes involved in this centrics or rings. The markers comprised only chromosome 21 process. material. Karyotypes were near-diploid and, besides dup(21), no The series of patients described here revealed the existence of other established chromosomal changes were observed. A total a distinct subgroup of older children with ALL and amplification of 20 patients, 1.5 and o0.5% among consecutive series of childhood and adult ALL respectively, showed this phenomen- of the AML1 gene, arising from partial duplication of the long on. Their median age was 9 years, white cell counts were low arm of chromosome 21, including the 21q22 region. and all had a pre-B/common immunophenotype. Although this series is not the first report of this abnormality, it is the largest, permitting a detailed description of the variety of morphological Materials and methods forms that duplicated chromosome 21 can assume. Leukemia (2003) 17, 547–553. doi:10.1038/sj.leu.2402849 Patients Keywords: amplified AML1; acute lymphoblastic leukemia; duplicated chromosome 21 The 20 patients in this study emerged from a series of children and adults with a diagnosis of ALL entered to one of the Medical Research Council (MRC) ALL treatment trials, UKALL XI or ALL Introduction 97 for children aged 1–18 years inclusive, or UKALL XII for adults aged 15–55 years. White blood cell count (WBC), The AML1 (CBFA2) gene, located in the chromosomal band immunophenotyping and morphological classification were 21q22, has recently attracted a lot of interest in terms of its role carried out in the local referral centers and these data, including in leukemogenesis. AML1 is involved in a number of chromo- follow-up information, were collected by the Clinical Trial somal translocations in leukemia. Of particular note in acute Service Unit (CTSU), Oxford. In the current childhood trial, ALL lymphoblastic leukemia (ALL) is the t(12;21)(p13;q22), in which 97, no distinction was made between pre-B and common ALL. AML1 fuses to the TEL (ETV6) gene. This translocation accounts for approximately 25% of B-lineage ALL in children.1–4 Additional copies of AML1 have often been observed in acute Cytogenetics leukemia. Acquired trisomy 21, a frequent finding in childhood ALL, itself produces one extra copy of the gene. Structural Cytogenetic analysis of diagnostic bone marrow or peripheral rearrangements involving duplication of the long arm of blood samples was carried out in the regional cytogenetics chromosome 21, dup(21), have also been described.5–14 laboratories. The G-banded slides were reviewed at the Fluorescence in situ hybridization (FISH) techniques showed Leukaemia Research Fund UK Cancer Cytogenetics Group (UKCCG) Karyotype Database in Acute Leukaemia (Data- that extra copies of the AML1 gene were present on these 25 abnormal chromosomes.6,9–14 In one of two patients, for whom base). Karyograms were generated using MacKtype software the amplified regions were shown to extend beyond the AML1 (Applied Imaging International, UK) and the karyotypes were described according to the International System of Human gene in both centromeric and telomeric directions, the 26 amplification included the ERG and ETS2 genes.10 Cytogenetic Nomenclature. Amplification of AML1 has been reported in acute myeloid leukemia (AML), where structural rearrangements resulted in FISH partial gains of chromosome 21. Among seven cases, two had evolved from a prior myelodysplasia.15–18 Point mutations19–22 Interphase FISH screening is routinely carried out on all trial and cryptic chromosome 21 rearrangements associated with patients for the prognostically significant abnormalities, TEL/ AML1 or BCR/ABL fusion and rearrangements of the MLL gene. Correspondence: CJ Harrison, Leukaemia Research Fund Cytogenetics This is performed on the fixed cell suspensions used for Group, Cancer Sciences Division, University of Southampton, MP 822 s Duthie Building, Southampton General Hospital, Southampton SO16 cytogenetic analysis. The dual color probe kit, LSI TEL/AML1 6YD, UK; Fax: 44 (0)23 8079 6432 ES (Vysis, UK), designed to detect the translocation, 4Current address: Medical Research Council Human Genetics t(12;21)(p13;q22), was hybridized to cell suspensions according Unit, Edinburgh, UK to the manufacturer’s instructions. This kit contains a probe Received 12 September 2002; accepted 12 November 2002 spanning the AML1 gene at 21q22, labeled with Spectrum Amplification of AML1 on duplicated chromosome 21 L Harewood et al 548 Orange, and a second probe covering exons 1–4 of the TEL coupled device (CCD) camera (Photometrics, USA) and gene, labeled with Spectrum Green. analyzed using MacProbe and M-FISH software (Applied To confirm the presence of the AML1 gene within the Imaging International Ltd, UK) as appropriate. duplicated chromosome 21 regions, two exon-specific cosmid probes together covering the entire gene were hybridized individually onto interphase and, wherever possible, metaphase Results cells from each patient. Cosmid ICRF c103 CO664 contains exons 1–5 of AML1 and cosmid H11086 contains exons 6 and A total of 20 patients with multiple copies of the AML1 signal 7. These probes were directly labeled with Spectrum Red using a were identified during a routine interphase FISH screening Nick Translation kit (Vysis, UK). Slides with selected metaphases program using the LSIs TEL/AML1 ES probe (Figures 1a and b). were co-denatured with 0.04 mg of labeled probe in 10 mlof In all, 13 patients were part of a consecutive series of 870 Hybrisol VII solution (Appligene-Oncor, Qbiogene, UK) at 721C children, aged between 1 and 18 years, from which we for 2 min and hybridized at 371C overnight. They were then estimated the incidence of this abnormality to be 1.5%. Among washed in 0.4x SSC with 0.3% IGEPAL (Sigma, UK), followed by adults over the age of 19 years, the incidence was o0.5% (one 2 Â SSC with 0.1% IGEPAL at room temperature. Cells were out of 229 patients). Patients with one or two additional signals examined using a Zeiss Axioskop fluorescence microscope fitted corresponding to extra copies of chromosome 21 were with appropriate filters (Karl Zeiss, Germany). excluded. The karyotypes, clinical details and follow-up data Whole chromosome paints (wcp) (STAR*FISH, Cambio, UK) for all 20 patients are shown in Table 1. All patients were were applied to metaphases where possible to resolve the G- negative for TEL/AML1 fusion, for BCR/ABL fusion and for banded karyotypes. Multiplex-FISH (M-FISH) was performed on rearrangements of the MLL gene. patients 3956, 4178, 5607 and 5754 using the SpectraVysion 24 Since the AML1 probe of the LSIs TEL/AML1 ES kit is color chromosome painting kit (Vysis, UK). These probes were B500 kb size and extends beyond the 50 and 30 ends of the hybridized according to the manufacturers’ instructions. AML1 gene, exon-specific probes to AML1 were applied in FISH images from interphase and metaphase cells were order to verify that the gene itself was amplified. Although these captured using an Olympus BX microscope with a cooled cosmids spanned more than one exon of AML1 (ICRF c103 Figure 1 (a) LSIs TEL/AML1 ES probe on interphase nuclei from patient 2776. The AML1 signals are in red and the TEL signals are green. (b) LSIs TEL/AML1 ES probe on a metaphase from patient 3368. The normal chromosome 21 has a single red signal and the dup(21) has tandemly repeated signals along part of its length. The normal and dup(21) are painted with wcp 21 (yellow). (c) Cosmid ICRF c103 CO664 covering exons 1–5 and (d) cosmid H11086 covering exons 6 and 7 of AML1 hybridized to metaphases from patient 4623. Leukemia Table 1 Karyotypes and Clinical Details of Patients with dup(21) Patient no. Sex/age WBC Â 109/l EFS OS AML1 Form of Karyotype (years) (months) (months) signals/cell dup(21) 2423 M/10 2 36 60+ 6+ M 48,XY,+X,+14,ider(21)(q10)dup(21)(q?) 2776 F/7 17 19 51+ 4–6 R 47,XX,+X,der(21)r(21)(q?)dup(21)(q?) 3131 M/11 11 27 32 6+ M 46,XY,t(1;16)(q23;p13),ider(21)(q10)dup(21)(q?)/51,idem,+X,+3,+10,+14,+21 3368a M/20 6 3+ 3+ 5+ AL 46,XY,del(7)(p1?5),t(8;22)(q1?1;q13),dup(21)(q?) 3527 F/13 3 26+ 26+
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