Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma.

Cancer Cell
Authors
Keywords
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
Journal
Cancer Cell
Volume
24
Issue
6
Pages
777-90
Date Published
2013 Dec 09
ISSN
1878-3686
URL
DOI
10.1016/j.ccr.2013.11.003
PubMed ID
24332044
PubMed Central ID
PMC4018722
Links
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