Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma
Author(s)Chapuy, Bjoern; McKeown, Michael R.; Lin, Charles Y.; Monti, Stefano; Roemer, Margaretha G.M.; Qi, Jun; Rahl, Peter B.; Sun, Heather H.; Yeda, Kelly T.; Doench, John G.; Reichert, Elaine; Kung, Andrew L.; Rodig, Scott J.; Young, Richard A.; Shipp, Margaret A.; Bradner, James E.; Young, Richard A.; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
Chapuy, Bjoern, Michael R. McKeown, Charles Y. Lin, Stefano Monti, Margaretha G.M. Roemer, Jun Qi, Peter B. Rahl, Heather H. Sun, Kelly T. Yeda, John G. Doench, Elaine Reichert, Andrew L. Kung, Scott J. Rodig, Richard A. Young, Margaret A. Shipp, and James E. Bradner. "Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma." Cancer Cell 24:6 (December 2013), pp. 777-790.
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