Understanding Selective Downregulation of c-Myc Expression through Inhibition of General Transcription Regulators in Multiple Myeloma
Annual rept. 15 Jun 2013-14 Jun 2014
DANA-FARBER CANCER INST BOSTON MA
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Chemical inhibitors that affect regulators of chromatin and transcription have emerged as powerful candidates for targeted cancer therapy. Through analysis of the chromatin and transcriptional landscape of Multiple Myeloma MM, 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 in MM to promote tumorigenesis. Here we report the first comprehensive map of the chromatin and transcriptional landscape of MM in both cell lines and primary patient MM. Analysis of these maps revealed a striking asymmetry in the distribution of chromatin co-activators, most notably at a set of clustered enhancer regions we have termed super-enhancers which contain disproportionate levels of chromatin co-activators and are found near key oncogenes in MM. Due to their extreme occupancy by chromatin co-activators, target genes of super-enhancers are exquisitely sensitive to perturbations in chromatin co-activator binding, suggesting a mechanism underlying the observed selective downregulation of oncogene transcription by BET-bromodomain inhibitors, a class of inhibitors currently in clinical trials. In other tumor systems, super-enhancers associate with tumor specific oncogenes and dependencies and provide a rationale for super-enhancer mapping to characterize tumor oncogees and dependencies.
- Anatomy and Physiology
- Medicine and Medical Research