A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.

Biomarkers, Tumor Brain Neoplasms / diagnosis Cell Cycle / genetics Cell Transformation, Neoplastic / drug effects Chromosomes, Human, Pair 19 Chromosomes, Human, Pair 2 DNA Copy Number Variations Enhancer Elements, Genetic Epigenesis, Genetic Gene Expression Regulation Gene Regulatory Networks Genetic Association Studies Genetic Predisposition to Disease Humans MicroRNAs / genetics Models, Biological Multigene Family N-Myc Proto-Oncogene Protein / genetics Neoplasms, Germ Cell and Embryonal / diagnosis Oncogenes RNA-Binding Proteins / genetics
C19MC ETMR LIN28A MYCN brain tumor cell-cycle epigenetics microRNA super-enhancer therapeutics

Journal

Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617

Informations de publication

Date de publication:
08 07 2019
Historique:
received: 11 02 2019
revised: 26 04 2019
accepted: 03 06 2019
entrez: 10 7 2019
pubmed: 10 7 2019
medline: 31 3 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ccell.2019.06.002 PMID: 31287992
pubmed: 31287992
pii: S1535-6108(19)30293-4
doi: 10.1016/j.ccell.2019.06.002
pii:
doi:

Substances chimiques

Biomarkers, Tumor 0
Lin28A protein, human 0
MicroRNAs 0
N-Myc Proto-Oncogene Protein 0
RNA-Binding Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

51-67.e7

Subventions

Organisme : CIHR
ID : 137011
Pays : Canada

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

Auteurs

Patrick Sin-Chan (P)

Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.

Iqra 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.

Tannu 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.

Ben Ho (B)

Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.

Xiaolian Fan (X)

Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.

Irtisha Singh (I)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Yuchen Du (Y)

Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.

Mei Lu (M)

Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.

Neilket Patel (N)

Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.

Jonathon Torchia (J)

Princess Margaret Cancer Center-OICR Translational Genomics Laboratory, Ontario Institute for Cancer Research, Toronto, ON M5G0A3, Canada.

Dean Popovski (D)

Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G0A4, Canada.

Maryam Fouladi (M)

Division of Oncology, Department of Cancer and Blood Diseases, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.

Paul 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.

Jordan R 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.

Sarah Leary (S)

Department of Hematology-Oncology, Seattle Children's Hospital, Seattle, WA 98105, USA.

Lindsey M Hoffman (LM)

Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.

Jean M Mulcahy Levy (JM)

Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.

Alvaro Lassaletta (A)

Pediatric Hematology and Oncology Department, Hospital Infantil Universitario Niño Jesús, Madrid 28009, Spain.

Palma Solano-Paez (P)

Department of Pediatric Oncology, Hospital Infantil Virgen del Rocio, Seville 41013, Spain.

Eloy Rivas (E)

Department of Pathology, Neuropathology Division, Hospital Universitario Virgen del Rocio, Seville 41013, Spain.

Alyssa Reddy (A)

University of Alabama at Birmingham, Birmingham, AL 35294, USA.

G Yancey Gillespie (GY)

Department of Neurosurgery, University of Alabama at Birmingham, Birmingham AL 35294, USA.

Nalin Gupta (N)

Department of Neurological Surgery, University of California, San Francisco, CA 94143-0112, USA.

Timothy E Van Meter (TE)

Department of Pediatrics, Virginia Commonwealth University, Richmond, VA 23298-0631, USA.

Hideo Nakamura (H)

Department of Neurosurgery, Kurume University, Fukuoka 830-0011, Japan.

Tai-Tong Wong (TT)

Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan.

Young-Shin Ra (YS)

Department of Neurosurgery, Asan Medical Center, Seoul 138-736, Korea.

Seung-Ki Kim (SK)

Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 03080, Korea.

Luca Massimi (L)

Department of Neurosurgery, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy.

Richard G Grundy (RG)

Children's Brain Tumor Research Centre, Queen's Medical Centre University of Nottingham, Nottingham NG72UH, UK.

Jason 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.

Donna Johnston (D)

Division of Hematology/Oncology, Children's Hospital of Eastern Ontario, Ottawa, ON K1H8L1, Canada.

Jennifer Chan (J)

Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB T2N1N4, Canada.

Lucie Lafay-Cousin (L)

Department of Pediatric Oncology, Alberta Children's Hospital, Calgary, AB T3B6A8, Canada.

Eugene I Hwang (EI)

Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC 20010, USA.

Yin Wang (Y)

Department of Neuropathology Huashan Hospital, Fudan University, Shanghai 200040, China.

Daniel Catchpoole (D)

The Tumor Bank, Children's Cancer Research Unit, Kids Research, the Children's Hospital at Westmead, Westmead, NSW 2145, Australia.

Jean Michaud (J)

Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON K1H8M5, Canada.

Benjamin Ellezam (B)

Department of Pathology, CHU Sainte-Justine Research Center, Université de Montréal, Montréal, QC H3T1C5, Canada.

Ramya Ramanujachar (R)

Paediatric Haematology and Oncology, Southampton Children's Hospital, Southampton SO166YD, UK.

Holly Lindsay (H)

Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.

Michael D 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.

Cynthia E 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.

Eric Bouffet (E)

Division of Hematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON M5G0A4, Canada.

Nada Jabado (N)

Departments of Pediatrics and Human Genetics, McGill University, Montréal, QC H3A0C7, Canada.

Sheila K Singh (SK)

McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S4K1, Canada.

Claudia L Kleinman (CL)

Departments of Pediatrics and Human Genetics, McGill University, Montréal, QC H3A0C7, Canada.

Dalia Barsyte-Lovejoy (D)

Structural Genomics Consortium, University of Toronto, Toronto, ON M5G1L7, Canada.

Xiao-Nan 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.

Peter B 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.

Charles Y Lin (CY)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Stephen C Mack (SC)

Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.

Jeremy N Rich (JN)

Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, CA 92093, USA.

Annie Huang (A)

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; Division of Hematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON M5G0A4, Canada; Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON M5G1L7, Canada. Electronic address: annie.huang@sickkids.ca.

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Classifications MeSH

questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Cycle cellulaire › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Carcinogenèse › Transformation cellulaire néoplasique › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Chromosomes › Chromosomes de mammifère › Chromosomes humains › Chromosomes humains 19-20 › Chromosomes humains de la paire 19 › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Chromosomes › Chromosomes de mammifère › Chromosomes humains › Chromosomes humains 1-3 › Chromosomes humains de la paire 2 › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Variation structurale du génome › Variations de nombre de copies de segment d'ADN › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Éléments activateurs (génétique) › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Séquences d'acides nucléiques régulatrices › Réseaux de régulation génique › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Études d'associations génétiques › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › microARN › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Famille multigénique › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines › Protéine du proto-oncogène N-Myc › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs embryonnaires et germinales › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Gènes tumoraux › Oncogènes › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › A C19MC-LIN28A-MYCN Oncogenic Circuit Driven...