Project description:Therapy-related acute myeloid leukemia (t-AML) is a severe complication of the cytotoxic therapy used for primary cancer treatment. The outcome of these patients is poor compared to people who develop de novo acute myeloid leukemia (p-AML). Chromosome abnormalities in t-AML are partly dependent on the induction agent. Partial or total losses of chromosome 5 and/or 7 are observed after therapy with alkylating agents. Balanced translocations, most of which involve 11q23 with MLL rearrangement, are found after treatment with the topoisomerase II inhibitor. Complex cases are also more frequent. The aim of this study was to compare t-AML to p-AML using high-resolution array CGH in order to identify gene-specific copy number abnormalities (CNA). Thirty t-AML versus thirty-six p-AML patient samples were studied. In t-AML, 99 CNAs were observed with 63 losses and 36 gains while the mean number was 3,3 per case. In p-AML, 64 CNAs were observed with 30 losses and 34 gains with a mean number of 1.78 per case. A few very complex cases (>8 chromosomal abnormalities) contributed considerably to the chromosomal burden in p-AML. Several minimal critical regions (MCR) that contain proteins and microRNA genes implicated in leukemogenesis were found in t-AML. On 7p15.2, a HOXA gene cluster involved in the processes of hematopoietic progenitor cell development and leukemogenesis was recurrently gained. Loss of a 5 Mb MCR located on 5q31.3q32 (142,91-148,19 Mb) was found distal to a previously described MCR; it harbored 29 genes. A 40kb deleted MCR pointed to RUNX1 on 21q22, a gene coding for a transcription factor implicated in frequent rearrangements in leukemia and in familial thrombocytopenia with susceptibility to AML. The sequence revealed no abnormality in 3 patients and a mutation in one patient, resulting in complete deficiency of RUNX1. In de novo AML a gain of 21q22<38,41-39,36> harboring ERG and ETS2 was observed in two patients with very complex rearrangements.

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Genome-wide Genotyping of Acute Myeloid Leukemia with Translocation t(9;11)(p22;q23) Reveals Novel Recurrent Genomic Alterations

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