title: An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma.
abstract: Translocation events are frequent in cancer and may create chimeric fusions or 'regulatory rearrangements' that drive oncogene overexpression. Here we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a recurrent theme in adenoid cystic carcinoma (ACC). Whole-genome sequencing data and chromatin maps highlight distinct chromosomal rearrangements that juxtapose super-enhancers to the MYB locus. Chromosome conformation capture confirms that the translocated enhancers interact with the MYB promoter. Remarkably, MYB protein binds to the translocated enhancers, creating a positive feedback loop that sustains its expression. MYB also binds enhancers that drive different regulatory programs in alternate cell lineages in ACC, cooperating with TP63 in myoepithelial cells and a Notch program in luminal epithelial cells. Bromodomain inhibitors slow tumor growth in ACC primagraft models in vivo. Thus, our study identifies super-enhancer translocations that drive MYB expression and provides insight into downstream MYB functions in alternate ACC lineages.
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Yotam
authors.identifier: http://orcid.org/0000-0003-1725-2995
authors.initials: Y
authors.lastname: Drier
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cotton
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Kaylyn E
authors.initials: KE
authors.lastname: Williamson
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Gillespie
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Russell J H
authors.initials: RJ
authors.lastname: Ryan
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kluk
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Carey
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Amir H
authors.initials: AH
authors.lastname: Afrogheh
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Faquin
authors.affiliation: Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Lurdes
authors.initials: L
authors.lastname: Queimado
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, Texas, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wick
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Moskaluk
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Knoechel
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
mesh_terms: D003528:Carcinoma, Adenoid Cystic / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020626:Oncogene Proteins v-myb / Q000096:biosynthesis* / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
chemical_list: D002843:Chromatin; D020626:Oncogene Proteins v-myb; D015514:Oncogene Proteins, Fusion; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
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