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Cancer Cell DOI:10.1016/j.ccr.2013.11.003

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

Publication TypeJournal Article
Year of Publication2013
AuthorsChapuy, B, McKeown, MR, Lin, CY, Monti, S, Roemer, MGM, Qi, J, Rahl, PB, Sun, HH, Yeda, KT, Doench, JG, Reichert, E, Kung, AL, Rodig, SJ, Young, RA, Shipp, MA, Bradner, JE
JournalCancer Cell
Date Published2013 Dec 09
KeywordsAzepines, DNA-Binding Proteins, Enhancer Elements, Genetic, Genes, myc, Humans, Lymphoma, Large B-Cell, Diffuse, Nuclear Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-6, Trans-Activators, Transcription Factors, Transcription, Genetic, Triazoles

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.


Alternate JournalCancer Cell
PubMed ID24332044
PubMed Central IDPMC4018722
Grant ListP50 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