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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.
Affiliation
  • Chapuy B; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • McKeown MR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • Lin CY; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • Monti S; Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA 02118, USA.
  • Roemer MG; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • Qi J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • Rahl PB; Whitehead Institute of Genome Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Sun HH; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Yeda KT; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • Doench JG; Broad Institute, Cambridge, MA 02142, USA.
  • Reichert E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • Kung AL; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Rodig SJ; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Young RA; Whitehead Institute of Genome Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Shipp MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: margaret_shipp@dfci.harvard.edu.
  • Bradner JE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: james_bradner@dfci.harvard.edu.
Cancer Cell ; 24(6): 777-90, 2013 Dec 09.
Article in En | MEDLINE | ID: mdl-24332044
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / Nuclear Proteins / Lymphoma, Large B-Cell, Diffuse / Enhancer Elements, Genetic Type of study: Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2013 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / Nuclear Proteins / Lymphoma, Large B-Cell, Diffuse / Enhancer Elements, Genetic Type of study: Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2013 Document type: Article Affiliation country: United States