Journal
CANCER CELL
Volume 24, Issue 6, Pages 777-790Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2013.11.003
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Funding
- National Institutes of Health
- Leukemia & Lymphoma Society
- Damon-Runyon Cancer Research Foundation
- Broad New Idea Award
- William Lawrence and Blanche Hughes Foundation
- American Society of Hematology
- Department of Defense [CDMRP CA120184]
- American Cancer Society [PF-11-042-01-DMC]
- German Research Foundation [DFG Ch 735/1-1]
- Syros Pharmaceuticals
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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.
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