Mechanisms for the development of therapy-related leukaemia caused by topoisomerase inhibitors

Abstract

Leukemia is a blood cancer that originates in the blood and bone marrow. Therapy-related leukemia is a leukemia associated with prior chemotherapy. Cancer therapy with DNA-topoisomerase II inhibitors is one of the most effective among chemotherapies. However, its side effect can be the development of secondary leukemia, characterized by chromosomal rearrangements involving the AML1 or MLL gene. The set of recurrent translocations in such leukemia differs from the set of chromosomal rearrangements in other neoplasia. We review the factors that drive the translocations upon treatment of cells with DNA-topoisomerase inhibitors. Such factors primarily include the mobility of double-strand DNA ends prior to translocation and the gain of functions of the fusion proteins that are formed in the cell as a result of translocation.