| Literature DB >> 24332044 |
Bjoern Chapuy1, Michael R McKeown1, Charles Y Lin1, Stefano Monti2, Margaretha G M Roemer1, Jun Qi1, Peter B Rahl3, Heather H Sun4, Kelly T Yeda1, John G Doench5, Elaine Reichert1, Andrew L Kung6, Scott J Rodig4, Richard A Young3, Margaret A Shipp7, James E Bradner8.
Abstract
Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of bromodomain and extra-terminal domain (BET) proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of bromodomain 4 (BRD4) at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease.Entities:
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Year: 2013 PMID： 24332044 PMCID： PMC4018722 DOI： 10.1016/j.ccr.2013.11.003
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743