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

. 2015 Dec 14;28(6):715-729.

doi: 10.1016/j.ccell.2015.10.005. Epub 2015 Nov 25.

Fiona J Coutinho 2, Robert J Vanner 2, Tenzin Gayden 3, Stephen C Mack 4, Alex Murison 5, Marc Remke 1, Ren Li 6, Naoya Takayama 5, Kinjal Desai 7, Lilian Lee 1, Xiaoyang Lan 2, Nicole I Park 2, Dalia Barsyte-Lovejoy 8, David Smil 8, Dominik Sturm 9, Michelle M Kushida 1, Renee Head 1, Michael D Cusimano 10, Mark Bernstein 11, Ian D Clarke 1, John E Dick 5, Stefan M Pfister 9, Jeremy N Rich 12, Cheryl H Arrowsmith 8, Michael D Taylor 13, Nada Jabado 3, David P Bazett-Jones 6, Mathieu Lupien 14, Peter B Dirks 15

Affiliations

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

Free article

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

Marco Gallo et al. Cancer Cell. 2015.

Free article

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.

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Comment in

• Glioma Stem-like Cells Keep Their H3.3 Variant Levels at Bay.
  Becher OJ, Holland EC. Becher OJ, et al. Cancer Cell. 2015 Dec 14;28(6):679-680. doi: 10.1016/j.ccell.2015.12.001. Cancer Cell. 2015. PMID: 26678332

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