Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations

Chromosomal aberrations are frequently associated with therapy-related myel odysplastic syndromes and acute myelogenous leukemia (t-MDS/AML) and are th ought to result from exposure to genotoxic drugs, including alkylating agen ts and DNA topoisomerase II poisons. The NUP98 gene on chromosome band 11p1 5 is involved in several different chromosomal aberrations that have been a ssociated with t-MDS/AML. We have cloned the translocation breakpoints from two cases of t-MDS harboring a (11;20)(p15;q11). Sequence analysis of the breakpoints from both cases revealed almost perfectly balanced translocatio ns between NUP98 and TOP1. There were no known recombinogenic sequences ide ntified at or near the breakpoints. However, four bp microduplications pres ent at the translocation crossover points suggested that these translocatio ns may have been initiated by 4 bp staggered double-stranded DNA breaks, wh ich are known to be associated with the action of topoisomerase II. Given t he history of patient exposure to topoisomerase II poisons, and the fact th at these drugs stabilize staggered breaks with a 4 bp overhang, it seems po ssible that drug-induced topoisomerase II cleavage and subunit exchange was involved in these translocations. These results suggest that NUP98 is a re current target for therapy-related malignancies induced by multiagent chemo therapy, and suggest a role for DNA topoisomerase II poisons in the generat ion of these translocations. Published 2000 Wiley-Liss, Inc.dagger