Convergence of BMI1 and CHD7 on ERK Signaling in Medulloblastoma
Sara Badodi,
Adrian Dubuc,
Xinyu Zhang,
Gabriel Rosser,
Mariane Da Cunha Jaeger,
Michelle M. Kameda-Smith,
Anca Sorana Morrissy,
Paul Guilhamon,
Philipp Suetterlin,
Xiao-Nan Li,
Loredana Guglielmi,
Ashirwad Merve,
Hamza Farooq,
Mathieu Lupien,
Sheila K. Singh,
M. Albert Basson,
Michael D. Taylor,
Silvia Marino
Affiliations
Sara Badodi
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
Adrian Dubuc
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, 101 College Street, TMDT-11-401M, Toronto, ON M5G 1L7, Canada
Xinyu Zhang
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
Gabriel Rosser
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
Mariane Da Cunha Jaeger
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
Michelle M. Kameda-Smith
Pediatric Neurosurgery, Department of Surgery, McMaster Children’s Hospital and McMaster Stem Cell & Cancer Research Institute, MDCL 5027, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada
Anca Sorana Morrissy
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, 101 College Street, TMDT-11-401M, Toronto, ON M5G 1L7, Canada
Paul Guilhamon
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada
Philipp Suetterlin
Department of Craniofacial Development and Stem Cell Biology, King’s College London, Floor 27, Guy’s Hospital Tower Wing, London SE1 9RT, UK
Xiao-Nan Li
Texas Children’s Cancer Centre, Texas Children’s Hospital, Baylor College of Medicine, 6621 Fannin Street, MC-3-3320, Houston, TX 77479, USA
Loredana Guglielmi
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
Ashirwad Merve
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
Hamza Farooq
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, 101 College Street, TMDT-11-401M, Toronto, ON M5G 1L7, Canada
Mathieu Lupien
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada
Sheila K. Singh
Pediatric Neurosurgery, Department of Surgery, McMaster Children’s Hospital and McMaster Stem Cell & Cancer Research Institute, MDCL 5027, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada
M. Albert Basson
Department of Craniofacial Development and Stem Cell Biology, King’s College London, Floor 27, Guy’s Hospital Tower Wing, London SE1 9RT, UK
Michael D. Taylor
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, 101 College Street, TMDT-11-401M, Toronto, ON M5G 1L7, Canada
Silvia Marino
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK; Corresponding author
Summary: We describe molecular convergence between BMI1 and CHD7 in the initiation of medulloblastoma. Identified in a functional genomic screen in mouse models, a BMI1High;CHD7Low expression signature within medulloblastoma characterizes patients with poor overall survival. We show that BMI1-mediated repression of the ERK1/2 pathway leads to increased proliferation and tumor burden in primary human MB cells and in a xenograft model, respectively. We provide evidence that repression of the ERK inhibitor DUSP4 by BMI1 is dependent on a more accessible chromatin configuration in G4 MB cells with low CHD7 expression. These findings extend current knowledge of the role of BMI1 and CHD7 in medulloblastoma pathogenesis, and they raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of MB with low expression levels of CHD7. : Badodi et al. find convergence of the chromatin modifiers BMI1 and CHD7 in medulloblastoma pathogenesis, and they show that this pathway regulates tumor proliferation and growth via ERK signaling. Keywords: BMI1, CHD7, DUSP4, ERK, medulloblastoma, PcG genes, mouse models, epigenetics, chromatin
