title: Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma.
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.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Bjoern
authors: B
authors: Chapuy
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Michael R
authors: MR
authors: McKeown
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Charles Y
authors: CY
authors: Lin
authors: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors: Stefano
authors: S
authors: Monti
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Margaretha G M
authors: MG
authors: Roemer
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Jun
authors: J
authors: Qi
authors: Whitehead Institute of Genome Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors: Peter B
authors: PB
authors: Rahl
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Heather H
authors: HH
authors: Sun
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Kelly T
authors: KT
authors: Yeda
authors: Broad Institute, Cambridge, MA 02142, USA.
authors: John G
authors: JG
authors: Doench
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Elaine
authors: E
authors: Reichert
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Andrew L
authors: AL
authors: Kung
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Scott J
authors: SJ
authors: Rodig
authors: Whitehead Institute of Genome Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors: Richard A
authors: RA
authors: Young
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: margaret_shipp@dfci.harvard.edu.
authors: Margaret A
authors: MA
authors: Shipp
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: james_bradner@dfci.harvard.edu.
authors: James E
authors: JE
authors: Bradner
mesh_terms: D001381:Azepines / Q000494:pharmacology; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000235:genetics; D004742:Enhancer Elements, Genetic; D016259:Genes, myc; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051560:Proto-Oncogene Proteins c-bcl-6; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D015534:Trans-Activators; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C084103:BCL6 protein, human; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C091546:POU2AF1 protein, human