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Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations
Author(s) -
Ahuja Harish G.,
Felix Carolyn A.,
Aplan Peter D.
Publication year - 2000
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/1098-2264(2000)9999:9999<::aid-gcc1013>3.0.co;2-t
Subject(s) - chromosomal translocation , topoisomerase , biology , breakpoint , dna , genetics , etoposide , leukemia , chromosome , gene , microbiology and biotechnology , cancer research , chemotherapy
Abstract Chromosomal aberrations are frequently associated with therapy‐related myelodysplastic syndromes and acute myelogenous leukemia (t‐MDS/AML) and are thought to result from exposure to genotoxic drugs, including alkylating agents and DNA topoisomerase II poisons. The NUP98 gene on chromosome band 11p15 is involved in several different chromosomal aberrations that have been associated with t‐MDS/AML. We have cloned the translocation breakpoints from two cases of t‐MDS harboring a t(11;20)(p15;q11). Sequence analysis of the breakpoints from both cases revealed almost perfectly balanced translocations between NUP98 and TOP1 . There were no known recombinogenic sequences identified at or near the breakpoints. However, four bp microduplications present at the translocation crossover points suggested that these translocations may have been initiated by 4 bp staggered double‐stranded DNA breaks, which are known to be associated with the action of topoisomerase II. Given the history of patient exposure to topoisomerase II poisons, and the fact that these drugs stabilize staggered breaks with a 4 bp overhang, it seems possible that drug‐induced topoisomerase II cleavage and subunit exchange was involved in these translocations. These results suggest that NUP98 is a recurrent target for therapy‐related malignancies induced by multiagent chemotherapy, and suggest a role for DNA topoisomerase II poisons in the generation of these translocations. Published 2000 Wiley‐Liss, Inc.