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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Azepines / pharmacology
  • Cell Cycle Proteins
  • DNA-Binding Proteins / genetics
  • Enhancer Elements, Genetic*
  • Genes, myc
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Nuclear Proteins / genetics*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-bcl-6
  • Trans-Activators / physiology
  • Transcription Factors / genetics*
  • Transcription, Genetic
  • Triazoles / pharmacology

Substances

  • (+)-JQ1 compound
  • Azepines
  • BCL6 protein, human
  • BRD4 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • POU2AF1 protein, human
  • Proto-Oncogene Proteins c-bcl-6
  • Trans-Activators
  • Transcription Factors
  • Triazoles

Associated data

  • GEO/GSE45630
  • GEO/GSE46663