title: MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin.
abstract: Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Gallo
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Coutinho
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Vanner
authors.affiliation: Departments of Pediatrics and Human Genetics, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3H 1P4, Canada.
authors.forename: Tenzin
authors.initials: T
authors.lastname: Gayden
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, OH 44195, USA; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mack
authors.affiliation: Ontario Institute for Cancer Research and Princess Margaret Cancer Centre-University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Murison
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Ren
authors.initials: R
authors.lastname: Li
authors.affiliation: Ontario Institute for Cancer Research and Princess Margaret Cancer Centre-University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Naoya
authors.initials: N
authors.lastname: Takayama
authors.affiliation: Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03755, USA.
authors.forename: Kinjal
authors.initials: K
authors.lastname: Desai
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Lilian
authors.initials: L
authors.lastname: Lee
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Lan
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Nicole I
authors.initials: NI
authors.lastname: Park
authors.affiliation: Ontario Institute for Cancer Research and Princess Margaret Cancer Centre-University Health Network, Toronto, ON M5G 1L7, Canada; Structural Genomics Consortium, Toronto, ON M5G 1L7, Canada.
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.affiliation: Ontario Institute for Cancer Research and Princess Margaret Cancer Centre-University Health Network, Toronto, ON M5G 1L7, Canada; Structural Genomics Consortium, Toronto, ON M5G 1L7, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Smil
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Sturm
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Kushida
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Renee
authors.initials: R
authors.lastname: Head
authors.affiliation: Division of Neurosurgery, University of Toronto, Toronto, ON M5S 1A8, Canada; St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cusimano
authors.affiliation: Division of Neurosurgery, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto Western Hospital, Toronto, ON M5T 2S8, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Bernstein
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Clarke
authors.affiliation: Ontario Institute for Cancer Research and Princess Margaret Cancer Centre-University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Ontario Institute for Cancer Research and Princess Margaret Cancer Centre-University Health Network, Toronto, ON M5G 1L7, Canada; Structural Genomics Consortium, Toronto, ON M5G 1L7, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Neurosurgery, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Departments of Pediatrics and Human Genetics, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3H 1P4, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: David P
authors.initials: DP
authors.lastname: Bazett-Jones
authors.affiliation: Ontario Institute for Cancer Research and Princess Margaret Cancer Centre-University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: mlupien@uhnres.utoronto.ca.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.affiliation: Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Neurosurgery, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: peter.dirks@sickkids.ca.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dirks
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D000066673:Cell Self Renewal / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D006657:Histones; C460660:KMT2E protein, human