%0 Journal Article
%A Gallo, Marco
%A Coutinho, Fiona J
%A Vanner, Robert J
%A Gayden, Tenzin
%A Mack, Stephen C
%A Murison, Alex
%A Remke, Marc
%A Li, Ren
%A Takayama, Naoya
%A Desai, Kinjal
%A Lee, Lilian
%A Lan, Xiaoyang
%A Park, Nicole I
%A Barsyte-Lovejoy, Dalia
%A Smil, David
%A Sturm, Dominik
%A Kushida, Michelle M
%A Head, Renee
%A Cusimano, Michael D
%A Bernstein, Mark
%A Clarke, Ian D
%A Dick, John E
%A Pfister, Stefan
%A Rich, Jeremy N
%A Arrowsmith, Cheryl H
%A Taylor, Michael D
%A Jabado, Nada
%A Bazett-Jones, David P
%A Lupien, Mathieu
%A Dirks, Peter B
%T MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin.
%J Cancer cell
%V 28
%N 6
%@ 1535-6108
%C Cambridge, Mass.
%I Cell Press
%M DKFZ-2017-02586
%P 715 - 729
%D 2015
%X 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.
%K Antineoplastic Agents (NLM Chemicals)
%K DNA-Binding Proteins (NLM Chemicals)
%K Histones (NLM Chemicals)
%K MLL5 protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:26626085
%R 10.1016/j.ccell.2015.10.005
%U https://inrepo02.dkfz.de/record/126558