MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin

Marco Gallo; Fiona J Coutinho; Robert J Vanner; Tenzin Gayden; Stephen C Mack; Alex Murison; Marc Remke; Ren Li; Naoya Takayama; Kinjal Desai; Lilian Lee; Xiaoyang Lan; Nicole I Park; Dalia Barsyte-Lovejoy; David Smil; Dominik Sturm; Michelle M Kushida; Renee Head; Michael D Cusimano; Mark Bernstein; Ian D Clarke; John E Dick; Stefan M Pfister; Jeremy N Rich; Cheryl H Arrowsmith; Michael D Taylor; Nada Jabado; David P Bazett-Jones; Mathieu Lupien; Peter B Dirks

doi:10.1016/j.ccell.2015.10.005

MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin

Cancer Cell. 2015 Dec 14;28(6):715-729. doi: 10.1016/j.ccell.2015.10.005. Epub 2015 Nov 25.

Authors

Marco Gallo¹, Fiona J Coutinho², Robert J Vanner², Tenzin Gayden³, Stephen C Mack⁴, Alex Murison⁵, Marc Remke¹, Ren Li⁶, Naoya Takayama⁵, Kinjal Desai⁷, Lilian Lee¹, Xiaoyang Lan², Nicole I Park², Dalia Barsyte-Lovejoy⁸, David Smil⁸, Dominik Sturm⁹, Michelle M Kushida¹, Renee Head¹, Michael D Cusimano¹⁰, Mark Bernstein¹¹, Ian D Clarke¹, John E Dick⁵, Stefan M Pfister⁹, Jeremy N Rich¹², Cheryl H Arrowsmith⁸, Michael D Taylor¹³, Nada Jabado³, David P Bazett-Jones⁶, Mathieu Lupien¹⁴, Peter B Dirks¹⁵

Affiliations

¹ 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.
² 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.
³ Departments of Pediatrics and Human Genetics, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3H 1P4, Canada.
⁴ 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.
⁵ Ontario Institute for Cancer Research and Princess Margaret Cancer Centre-University Health Network, Toronto, ON M5G 1L7, Canada.
⁶ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁷ Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03755, USA.
⁸ 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.
⁹ Division of Pediatric Neurooncology, German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany.
¹⁰ Division of Neurosurgery, University of Toronto, Toronto, ON M5S 1A8, Canada; St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
¹¹ Division of Neurosurgery, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto Western Hospital, Toronto, ON M5T 2S8, Canada.
¹² Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, OH 44195, USA.
¹³ 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.
¹⁴ 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.
¹⁵ 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.

PMID: 26626085
DOI: 10.1016/j.ccell.2015.10.005

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.

Publication types

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

MeSH terms

Adolescent
Adult
Animals
Antineoplastic Agents / pharmacology
Brain Neoplasms / drug therapy
Brain Neoplasms / genetics
Brain Neoplasms / metabolism*
Brain Neoplasms / mortality
Brain Neoplasms / pathology
Cell Differentiation
Cell Proliferation
Cell Self Renewal* / drug effects
Child
Child, Preschool
Chromatin Assembly and Disassembly* / drug effects
DNA Methylation
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Drug Design
Epigenesis, Genetic
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Glioblastoma / drug therapy
Glioblastoma / genetics
Glioblastoma / metabolism*
Glioblastoma / mortality
Glioblastoma / pathology
Histones / genetics
Histones / metabolism*
Humans
Kaplan-Meier Estimate
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy
Mutation
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology
Prognosis
RNA Interference
Signal Transduction
Time Factors
Transfection
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Young Adult

MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin

Authors

Affiliations

Abstract

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