Translocation Mechanism in Secondary Leukemias Following Topoisomerase II Poisons

More than 15 years after observations of an association between a distinct form of leukemia characterized by balanced chromosomal translocations involving band 11q23 and introduction of epipodophyllotoxins into clinical usage for anti-cancer treatment in the late1980s, the translocation mechanism is still debated. Epipodophyllotoxins and other anticancer drugs that have been linked to leukemias with various balanced translocations as a treatment complication share the property of being topoisomerase II poisons. In the early 1990s the MLL (ALL-1, HRX, hTRX1) gene was cloned by several groups at the genomic breakpoint junctions of translocations disrupting chromosome band 11q23. This paper will review evidence in favor of the hypothesis that topoisomerase II cleavage complexes induced by poisons of this enzyme damage DNA directly and lead to translocations in secondary leukemias with MLL translocations.