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: 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
• Journal: Cancer cell (Cancer Cell) Vol. 28 Issue 6 Pg. 715-729 (Dec 14 2015) ISSN: 1878-3686 [Electronic] United States
• PMID: 26626085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• DNA-Binding Proteins
• Histones
• KMT2E protein, human

Topics

• Adolescent
• Adult
• Animals
• Antineoplastic Agents (pharmacology)
• Brain Neoplasms (drug therapy, genetics, metabolism, mortality, 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, metabolism)
• Drug Design
• Epigenesis, Genetic
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Glioblastoma (drug therapy, genetics, metabolism, mortality, pathology)
• Histones (genetics, metabolism)
• Humans
• Kaplan-Meier Estimate
• Mice, Inbred NOD
• Mice, SCID
• Molecular Targeted Therapy
• Mutation
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Prognosis
• RNA Interference
• Signal Transduction
• Time Factors
• Transfection
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Young Adult