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Cancer Cell. 2013 Dec 9;24(6):777-90. doi: 10.1016/j.ccr.2013.11.003.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
2
Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA 02118, USA.
3
Whitehead Institute of Genome Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
4
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
5
Broad Institute, Cambridge, MA 02142, USA.
6
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: margaret_shipp@dfci.harvard.edu.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: james_bradner@dfci.harvard.edu.

Erratum in

  • Cancer Cell. 2014 Apr 14;25(4):545-6.

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.

PMID:
24332044
PMCID:
PMC4018722
DOI:
10.1016/j.ccr.2013.11.003
[Indexed for MEDLINE]
Free PMC Article
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