Systematic Approaches to Identify Actionable Epigenetic Vulnerabilities in Cancer

Chromatin deregulation is a major pathogenic mechanism that drives the formation of human cancer. Consequently, targeting of chromatin regulatory machineries is an attractive therapeutic strategy to selectively eliminate cancer cells. Our research seeks to comprehensively identify essential chromatin regulators in various hematological and solid tumors and understand underlying basic mechanisms that underlie such dependencies. In my presentation, I will discuss our recent efforts at utilizing CRISPR-Cas9 screening as a means to reveal essential protein domains in cancer cells. This approach should have broad utility in cancer drug target discovery and as a tool for investigating basic gene regulatory mechanisms. I will also discuss our latest work investigating the mechanism of BRD4 function in leukemia. We previously identified BRD4, a member of the BET family of bromodomain-containing proteins, as a drug target in leukemia and our ongoing work seeks to reveal underlying mechanisms of BRD4 function in this disease context. I will present our recent findings regarding the downstream effectors of BRD4 function that allow transcriptional activation, specifically in leukemia.