Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma.
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| 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. |
| Year of Publication | 2013
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| Journal | Cancer Cell
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| Volume | 24
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| Issue | 6
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| Pages | 777-90
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| Date Published | 2013 Dec 09
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| ISSN | 1878-3686
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| URL | |
| DOI | 10.1016/j.ccr.2013.11.003
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| PubMed ID | 24332044
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| PubMed Central ID | PMC4018722
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| Grant list | P50 CA100707 / CA / NCI NIH HHS / United States
R01 CA152314 / CA / NCI NIH HHS / United States
R01 CA176745 / CA / NCI NIH HHS / United States
U54 CA156732 / CA / NCI NIH HHS / United States
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