Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/103897 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1826210232067424256 |
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| author | 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. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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. |
| author_sort | Chapuy, Bjoern |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T14:46:33Z |
| format | Article |
| id | mit-1721.1/103897 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:46:33Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1038972022-09-29T10:29:25Z Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma 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. Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Young, Richard A. 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. Broad Institute of MIT and Harvard (Broad New Idea Award) American Society of Hematology William Lawrence and Blanche Hughes Foundation Damon Runyon Cancer Research Foundation Leukemia & Lymphoma Society of America National Institutes of Health (U.S.) United States. Department of Defense (CDMRP CA120184) American Cancer Society (PF-11-042-01-DMC) Deutsche Forschungsgemeinschaft (DFG Ch 735/1-1) 2016-08-11T16:02:42Z 2016-08-11T16:02:42Z 2013-12 2013-09 Article http://purl.org/eprint/type/JournalArticle 15356108 http://hdl.handle.net/1721.1/103897 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. https://orcid.org/0000-0001-8855-8647 en_US http://dx.doi.org/10.1016/j.ccr.2013.11.003 Cancer Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | 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. Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma |
| title | Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma |
| title_full | Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma |
| title_fullStr | Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma |
| title_full_unstemmed | Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma |
| title_short | Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma |
| title_sort | discovery and characterization of super enhancer associated dependencies in diffuse large b cell lymphoma |
| url | http://hdl.handle.net/1721.1/103897 https://orcid.org/0000-0001-8855-8647 |
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