Topoisomerase poisons, such as etoposide, are widely used drugs in clinic to treat a variety of cancers. Treatment with these drugs, has been associated, however, with increased risk of developing secondary therapy-related leukemias, driven by chromosome translocations of the MLL gene. Our aim is to identify how trapped topoisomerases are converted to double-strand breaks (DSBs) across the genome, how these breaks are getting repaired in the genomic and chromatin context and how illegitimate repair contributes to oncogenic MLL translocations. We also aim at identifying new factors involved in the removal of trapped topoisomerases from DNA. To achieve our goals, we will employ methodologies that are able to profile and quantify DSBs across the genome, high-throughput imaging tools to probe and quantify rare translocation events, and quantitative proteomics.
Dissecting molecular mechanisms of oncogenic, therapy-related MLL translocations