Understanding Selective Downregulation of c-Myc Expression through Inhibition of General Transcription Regulators in Multiple Myeloma
Technical Report,15 Jun 2013,30 Sep 2015
Dana-Farber Cancer Institute, Inc. Boston United States
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Through analysis of the chromatin and transcriptional landscape of Multiple Myeloma MM and other tumors, this project has endeavored to provide an explanatory mechanism for how treatment with inhibitors of chromatin regulators can selectively target oncogene transcription, and to understand how chromatin and transcription are altered to promote tumorigenesis. Here we report the discoveries that BET bromodomains are required to communicate enhancer mediated pro-inflammatory signal dependent transduction Brown et al., 2014, that translocations of the IgH enhancer to the MYC locus in MMexpose both enhancer driven and MYCE2F driven regulatory programs to BET bromodomain inhibition Fulciniti et al., in preparation, and that master transcription factors cooperate with one another and BET bromodomains to establish oncogenic state in MM and other tumors Lin et al., Nature in press. Inanticipation of clinical drug resistance to BET bromodomain inhibition, we identified an epigenetic mechanism of resistance in which hyper-phosphorylation of BET bromodomains enables tumor cells to recruit these proteins to chromatin independent of bromodomain activity Shu et al., Nature in press. These effortshave yielded insights into the dynamic transcriptional control of oncogenic cell state, the development of novel and extendable experimental andcomputational approaches, and therapeutic insights into the consequences of systemic in vivo BET bromodomain inhibition.