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

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

Author information

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.

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.

PMID:
26626085
DOI:
10.1016/j.ccell.2015.10.005
[Indexed for MEDLINE]
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