Abstract
Therapy-related acute leukemia (t-AML), is a severe complication of cytotoxic therapy used for primary cancer treatment. The outcome of these patients is poor, compared to people who develop de novo acute leukemia (p-AML). Cytogenetic abnormalities in t-AML are similar to those found in p-AML but present more frequent unfavorable karyotypes depending on the inducting agent. Losses of chromosome 5 or 7 are observed after alkylating agents while balanced translocations are found after topoisomerase II inhibitors. This study compared t-AML to p-AML using high resolution array CGH in order to find copy number abnormalities (CNA) at a higher resolution than conventional cytogenetics. More CNAs were observed in 30 t-AML than in 36 p-AML: 104 CNAs were observed with 63 losses and 41 gains (mean number 3.46 per case) in t-AML, while in p-AML, 69 CNAs were observed with 32 losses and 37 gains (mean number of 1.9 per case). In primary leukemia with a previously “normal” karyotype, 18% exhibited a previously undetected CNA, whereas in the (few) t-AML with a normal karyotype, the rate was 50%. Several minimal critical regions (MCRs) were found in t-AML and p-AML. No common MCRs were found in the two groups. In t-AML 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. In de novo AML, a 1Mb MCR harboring ERG and ETS2 was observed from patients with complex aCGH profiles. High resolution cytogenomics obtained by aCGH and similar techniques already published allowed us to characterize numerous non random chromosome abnormalities. This work supports the hypothesis that they can be classified into several categories: abnormalities common to all AML; those more frequently found in t-AML and those specifically found in p-AML.
Highlights
Therapy-related myeloblastic leukemia, including therapyrelated myelodysplasia, (t-AML), constitutes approximately 10% of AML and has several characteristic features [1,2]
Variations (CNV) were distinguished from Copy Number Abnormalities (CNA) based on various criteria: i) sequence size below 2 Mb; ii) the presence of repetitive identical breakpoints between patients; iii) the genes involved such as olfactory receptor genes, the NF1P1 locus or GSTT1 and iv) consultation of the Database of Genomic Variants [7]
The Copy Number Variations (CNV) As we were obliged to use a pool of normal DNA as a reference, Mendelian CNVs that are present throughout the entire genome [8], were revealed by the 244K aCGH
Summary
Therapy-related myeloblastic leukemia, including therapyrelated myelodysplasia, (t-AML), constitutes approximately 10% of AML and has several characteristic features [1,2]. The first one is due to prior therapy with alkylating agents (AA) or radiotherapy [1,2,3,4] It occurs generally after a latency period of 5 to 7 years. This kind of t-AML is often preceded by a preleukemic period of myelodysplasia (t-MDS). Drugs that target topoisomerase II (ATII), such as etoposide and anthracyclines may induce the second type of t-AML [1,2,3,4]. It occurs in a median of 2 years and is not preceded by MDS. Cytogenetic analysis shows a high frequency of rearrangements of chromosome band 11q23 and recurrent balanced rearrangements t(8;21), t(15;17) and inv(16) [1,2]
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