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A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.
Sin-Chan, Patrick; Mumal, Iqra; Suwal, Tannu; Ho, Ben; Fan, Xiaolian; Singh, Irtisha; Du, Yuchen; Lu, Mei; Patel, Neilket; Torchia, Jonathon; Popovski, Dean; Fouladi, Maryam; Guilhamon, Paul; Hansford, Jordan R; Leary, Sarah; Hoffman, Lindsey M; Mulcahy Levy, Jean M; Lassaletta, Alvaro; Solano-Paez, Palma; Rivas, Eloy; Reddy, Alyssa; Gillespie, G Yancey; Gupta, Nalin; Van Meter, Timothy E; Nakamura, Hideo; Wong, Tai-Tong; Ra, Young-Shin; Kim, Seung-Ki; Massimi, Luca; Grundy, Richard G; Fangusaro, Jason; Johnston, Donna; Chan, Jennifer; Lafay-Cousin, Lucie; Hwang, Eugene I; Wang, Yin; Catchpoole, Daniel; Michaud, Jean; Ellezam, Benjamin; Ramanujachar, Ramya; Lindsay, Holly; Taylor, Michael D; Hawkins, Cynthia E; Bouffet, Eric; Jabado, Nada; Singh, Sheila K; Kleinman, Claudia L; Barsyte-Lovejoy, Dalia; Li, Xiao-Nan; Dirks, Peter B.
Affiliation
  • Sin-Chan P; Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
  • Mumal I; Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S1A8, Canada.
  • Suwal T; Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S1A8, Canada.
  • Ho B; Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
  • Fan X; Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
  • Singh I; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Du Y; Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
  • Lu M; Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
  • Patel N; Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
  • Torchia J; Princess Margaret Cancer Center-OICR Translational Genomics Laboratory, Ontario Institute for Cancer Research, Toronto, ON M5G0A3, Canada.
  • Popovski D; Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
  • Fouladi M; Division of Oncology, Department of Cancer and Blood Diseases, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
  • Guilhamon P; Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
  • Hansford JR; Children's Cancer Centre, Royal Children's Hospital, Murdoch Children's Research Institute, Department of Pediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
  • Leary S; Department of Hematology-Oncology, Seattle Children's Hospital, Seattle, WA 98105, USA.
  • Hoffman LM; Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
  • Mulcahy Levy JM; Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
  • Lassaletta A; Pediatric Hematology and Oncology Department, Hospital Infantil Universitario Niño Jesús, Madrid 28009, Spain.
  • Solano-Paez P; Department of Pediatric Oncology, Hospital Infantil Virgen del Rocio, Seville 41013, Spain.
  • Rivas E; Department of Pathology, Neuropathology Division, Hospital Universitario Virgen del Rocio, Seville 41013, Spain.
  • Reddy A; University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Gillespie GY; Department of Neurosurgery, University of Alabama at Birmingham, Birmingham AL 35294, USA.
  • Gupta N; Department of Neurological Surgery, University of California, San Francisco, CA 94143-0112, USA.
  • Van Meter TE; Department of Pediatrics, Virginia Commonwealth University, Richmond, VA 23298-0631, USA.
  • Nakamura H; Department of Neurosurgery, Kurume University, Fukuoka 830-0011, Japan.
  • Wong TT; Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan.
  • Ra YS; Department of Neurosurgery, Asan Medical Center, Seoul 138-736, Korea.
  • Kim SK; Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 03080, Korea.
  • Massimi L; Department of Neurosurgery, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy.
  • Grundy RG; Children's Brain Tumor Research Centre, Queen's Medical Centre University of Nottingham, Nottingham NG72UH, UK.
  • Fangusaro J; Department of Pediatric Hematology and Oncology at Children's Healthcare of Atlanta and the Emory University School of Medicine, Atlanta, GA 30322, USA.
  • Johnston D; Division of Hematology/Oncology, Children's Hospital of Eastern Ontario, Ottawa, ON K1H8L1, Canada.
  • Chan J; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB T2N1N4, Canada.
  • Lafay-Cousin L; Department of Pediatric Oncology, Alberta Children's Hospital, Calgary, AB T3B6A8, Canada.
  • Hwang EI; Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC 20010, USA.
  • Wang Y; Department of Neuropathology Huashan Hospital, Fudan University, Shanghai 200040, China.
  • Catchpoole D; The Tumor Bank, Children's Cancer Research Unit, Kids Research, the Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
  • Michaud J; Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON K1H8M5, Canada.
  • Ellezam B; Department of Pathology, CHU Sainte-Justine Research Center, Université de Montréal, Montréal, QC H3T1C5, Canada.
  • Ramanujachar R; Paediatric Haematology and Oncology, Southampton Children's Hospital, Southampton SO166YD, UK.
  • Lindsay H; Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
  • Taylor MD; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S1A8, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
  • Hawkins CE; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S1A8, Canada; Department of Pathology, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
  • Bouffet E; Division of Hematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON M5G0A4, Canada.
  • Jabado N; Departments of Pediatrics and Human Genetics, McGill University, Montréal, QC H3A0C7, Canada.
  • Singh SK; McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S4K1, Canada.
  • Kleinman CL; Departments of Pediatrics and Human Genetics, McGill University, Montréal, QC H3A0C7, Canada.
  • Barsyte-Lovejoy D; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G1L7, Canada.
  • Li XN; Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Dirks PB; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S1A8, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
Cancer Cell ; 36(1): 51-67.e7, 2019 07 08.
Article in En | MEDLINE | ID: mdl-31287992
Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Chromosomes, Human, Pair 19 / Brain Neoplasms / Multigene Family / RNA-Binding Proteins / Neoplasms, Germ Cell and Embryonal / MicroRNAs / N-Myc Proto-Oncogene Protein Type of study: Diagnostic_studies / Prognostic_studies Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2019 Type: Article Affiliation country: Canada
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Chromosomes, Human, Pair 19 / Brain Neoplasms / Multigene Family / RNA-Binding Proteins / Neoplasms, Germ Cell and Embryonal / MicroRNAs / N-Myc Proto-Oncogene Protein Type of study: Diagnostic_studies / Prognostic_studies Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2019 Type: Article Affiliation country: Canada