title: Predisposition to therapy-related acute leukemia with balanced chromosomal translocations does not result from a major constitutive defect in DNA double-strand break end joining.
abstract: The frequency of acute myeloid leukemia (AML) with balanced chromosomal translocations arising after anticancer therapy with DNA-damaging agents such as DNA topoisomerase II inhibitors has increased over the last two decades. However, factors that predispose to these therapy-related disorders are still poorly defined. It has been reported that DNA double-strand break (DSB) repair by the non-homologous end-joining (NHEJ) pathway is impaired in myeloid leukemia cells. This led us to hypothesize that therapy-related AML (t-AML) may result from individual differences in the repair of DSBs generated by the treatment. We show here that DSB repair is accurate, in vivo, in non-tumoral cells derived from patients who developed t-AML with t(9;11) or t(15;17) translocation after treatment for a first cancer with DNA topoisomerase II inhibitors. These results indicate that a major constitutive defect in the NHEJ pathway is unlikely to predispose to t-AML with balanced chromosomal translocations.
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8126, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94 805 Villejuif Cedex, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Coiteux
authors.forename: Rosine
authors.initials: R
authors.lastname: Onclercq-Delic
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: Mounira
authors.initials: M
authors.lastname: Amor-Guéret
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D045744:Cell Line, Tumor; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004250:DNA Topoisomerases, Type II; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000188:drug therapy / Q000235:genetics*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II