Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma

详细信息    查看全文

• 作者：Bjoern Chapuy ; Michael聽R. McKeown ; Charles聽Y. Lin ; Stefano Monti ; Margaretha聽G.M. Roemer ; Jun Qi ; Peter聽B. Rahl ; Heather聽H. Sun ; Kelly聽T. Yeda ; John聽G. Doench ; Elaine Reichert ; Andrew聽L. Kung ; Scott聽J. Rodig ; Richard聽A. Young ; Margaret聽A. Shipp ; James聽E. Bradner
• 刊名：Cancer Cell
• 出版年：9 December, 2013
• 年：2013
• 卷：24
• 期：6
• 页码：777-790
• 全文大小：4504 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferencesl version="1.0" encoding="UTF-8"?>

lass="h3">Summary

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.