Mechanisms of Chromosomal Translocation

Clinical Sciences

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Abstract

We have divided this project into two portions. A) Chemotherapy-induced chromosome breakage. Both the AML1 and MLL genes are frequently translocated in patients who develop acute myeloid leukemia following treatment with chemotherapeutic regimens that incorporate topoisomerase II poisons. We have identified specific sites within the breakpoint cluster regions of both the AML1 and MLL genes which are uniquely sensitive to double strand DNA cleavage induced by topoisomerase II poisons. We have further demonstrated that cleavage at these two sites can also be induced through an apoptotic pathway. Our current hypothesis is that this site-specific cleavage occurs through cleavage of DNA at the base of chromatin loops, or scaffold (matrix) attachment regions (SARs or MARs). These SAR (MAR) regions may be preferentially cleaved due to chromatin accessibility, primary nucleotide sequence, or both. We have developed a model where the MLL breakpoint cluster region, and various deletion mutants, can be introduced into mammalian cells via episomal vectors to investigate these questions. We are attempting to develop a model system in which we can reproducibly induce chromosomal translocations in human hematopoietic cells in vitro through the use of genotoxic agents. B) Recombinogenic genomic regions. Despite thousands of studies based on recurrent, non-random chromosomal translocations, a fundamental question concerning these translocations remains unresolved. This question can be phrased as follows: "Do recurrent, non-random translocations occur between "recombinogenic" regions of the genome that are extraordinarily susceptible to breakage/religation events, or are the regions involved not particularly recombinogenic, but simply regions that lead to the production of oncogenic fusion proteins which confer a growth advantage to the cell." To help address this question, we plan to develop an in vitro system in which we can produce translocations that do not necessarily provide a growth advantage to the cell.