title: Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia.
abstract: Notch is needed for T-cell development and is a common oncogenic driver in T-cell acute lymphoblastic leukemia. The protooncogene c-Myc (Myc) is a critical target of Notch in normal and malignant pre-T cells, but how Notch regulates Myc is unknown. Here, we identify a distal enhancer located >1 Mb 3' of human and murine Myc that binds Notch transcription complexes and physically interacts with the Myc proximal promoter. The Notch1 binding element in this region activates reporter genes in a Notch-dependent, cell-context-specific fashion that requires a conserved Notch complex binding site. Acute changes in Notch activation produce rapid changes in H3K27 acetylation across the entire enhancer (a region spanning >600 kb) that correlate with Myc expression. This broad Notch-influenced region comprises an enhancer region containing multiple domains, recognizable as discrete H3K27 acetylation peaks. Leukemia cells selected for resistance to Notch inhibitors express Myc despite epigenetic silencing of enhancer domains near the Notch transcription complex binding sites. Notch-independent expression of Myc in resistant cells is highly sensitive to inhibitors of bromodomain containing 4 (Brd4), a change in drug sensitivity that is accompanied by preferential association of the Myc promoter with more 3' enhancer domains that are strongly dependent on Brd4 for function. These findings indicate that altered long-range enhancer activity can mediate resistance to targeted therapies and provide a mechanistic rationale for combined targeting of Notch and Brd4 in leukemia.
authors.affiliation: Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yashiro-Ohtani
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Hongfang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Departments of Biostatistics and Computational Biology and.
authors.forename: Chongzhi
authors.initials: C
authors.lastname: Zang
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Arnett
authors.affiliation: Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and.
authors.forename: Will
authors.initials: W
authors.lastname: Bailis
authors.affiliation: Department of Genetics, and.
authors.forename: Yugong
authors.initials: Y
authors.lastname: Ho
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Birgit
authors.initials: B
authors.lastname: Knoechel
authors.affiliation: Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanauze
authors.affiliation: Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and.
authors.forename: Lumena
authors.initials: L
authors.lastname: Louis
authors.affiliation: Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Forsyth
authors.affiliation: Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China 200092.
authors.forename: Sujun
authors.initials: S
authors.lastname: Chen
authors.affiliation: Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and.
authors.forename: Yoonjie
authors.initials: Y
authors.lastname: Chung
authors.affiliation: Department of Genetics, and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schug
authors.affiliation: Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Blobel
authors.affiliation: Department of Genetics, and.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Liebhaber
authors.affiliation: Broad Institute and Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; and.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Blacklow
authors.affiliation: Departments of Biostatistics and Computational Biology and.
authors.forename: Xiaole Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; wpear@mail.med.upenn.edu jaster@partners.org.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, and wpear@mail.med.upenn.edu jaster@partners.org.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
mesh_terms: D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D017930:Genes, Reporter; D016259:Genes, myc; D055106:Genome-Wide Association Study; D006657:Histones / Q000378:metabolism; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011487:Protein Conformation; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; C497570:RBPJ protein, human; C497571:Rbpj protein, mouse
keywords: Brd4; chromatin; enhancer; gene regulation; transcription