TY  - JOUR
AU  - Gallo, Marco
AU  - Coutinho, Fiona J
AU  - Vanner, Robert J
AU  - Gayden, Tenzin
AU  - Mack, Stephen C
AU  - Murison, Alex
AU  - Remke, Marc
AU  - Li, Ren
AU  - Takayama, Naoya
AU  - Desai, Kinjal
AU  - Lee, Lilian
AU  - Lan, Xiaoyang
AU  - Park, Nicole I
AU  - Barsyte-Lovejoy, Dalia
AU  - Smil, David
AU  - Sturm, Dominik
AU  - Kushida, Michelle M
AU  - Head, Renee
AU  - Cusimano, Michael D
AU  - Bernstein, Mark
AU  - Clarke, Ian D
AU  - Dick, John E
AU  - Pfister, Stefan
AU  - Rich, Jeremy N
AU  - Arrowsmith, Cheryl H
AU  - Taylor, Michael D
AU  - Jabado, Nada
AU  - Bazett-Jones, David P
AU  - Lupien, Mathieu
AU  - Dirks, Peter B
TI  - MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin.
JO  - Cancer cell
VL  - 28
IS  - 6
SN  - 1535-6108
CY  - Cambridge, Mass.
PB  - Cell Press
M1  - DKFZ-2017-02586
SP  - 715 - 729
PY  - 2015
AB  - 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.
KW  - Antineoplastic Agents (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - Histones (NLM Chemicals)
KW  - MLL5 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26626085
DO  - DOI:10.1016/j.ccell.2015.10.005
UR  - https://inrepo02.dkfz.de/record/126558
ER  -