Gallo, Marco, Coutinho, Fiona J., Vanner, Robert J., Gayden, Tenzin, Mack, Stephen C., Murison, Alex, Remke, Marc, Li, Ren, Takayama, Naoya, Desai, Kinjal, Lee, Lilian, Lan, Xiaoyang, Park, Nicole I., Barsyte-Lovejoy, Dalia, Smil, David, Sturm, Dominik, Kushida, Michelle M., Head, Renee, Cusimano, Michael D., Bernstein, Mark, Clarke, Ian D., Dick, John E., Pfister, Stefan M., Rich, Jeremy N., Arrowsmith, Cheryl H., Taylor, Michael D., Jabado, Nada, Bazett-Jones, David P., Lupien, Mathieu and Dirks, Peter B. (2015) MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin. Cancer Cell, 28 (6). pp. 715-729. ISSN 15356108

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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.

Item Type:	Article
Divisions:	Faculty of Liberal Arts & Sciences
Date Deposited:	21 Mar 2018 14:34
Last Modified:	02 Aug 2021 08:44
URI:	https://openresearch.ocadu.ca/id/eprint/2205

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