542 The Experimental Anti-cancer Drug Mitochondrially-targeted Vitamin E Succinate Inhibits Mitochondrial Transcription

Abstract

domain in germinal center B-cell like diffuse large B-cell lymphoma (GCBDLBCL) and follicular lymphoma suggests that these cancers might be dependent on altered EZH2 molecular function, the mutation facilitating the conversion of a H3K27 di-methylated to a tri-methylated state. Inhibition of the EZH2 catalytic activity will provide a new therapeutic approach to treat human cancers, especially lymphomas carrying activating mutations. Constellation has identified, characterized and optimized potent, selective and reversible EZH2 small molecule inhibitors as well as studied the biological impact of such inhibition. We find that pharmacological inhibition of EZH2 causes cell viability defects with cell lines harboring EZH2 mutations being the most sensitive. Genome-wide mapping of EZH2 and H3K27me3 sites in the absence and presence of the compound revealed that the EZH2 inhibitor caused significant changes to the local chromatin modification landscape, however only a subset of these alterations translated into gene expression changes. The EZH2-controlled gene signature and the functional impact of altered expression on GCBDLBCL cell survival will be discussed.