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

• Published in: Cancer cell Vol. 28; no. 6; pp. 715 - 729
• Main Authors: 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, Dirks, Peter B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-12-2015
• Subjects: Adolescent; Adult; Animals; Antineoplastic Agents - pharmacology; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - mortality; Brain Neoplasms - 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; DNA-Binding Proteins - metabolism; Drug Design; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - mortality; Glioblastoma - pathology; Histones - genetics; Histones - metabolism; Humans; Kaplan-Meier Estimate; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Mutation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Prognosis; RNA Interference; Signal Transduction; Time Factors; Transfection; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Young Adult
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2015.10.005

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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•DNA methylomes of adult GBM self-renewing cells resemble H3.3-mutated pediatric GBM•MLL5 represses H3.3 levels in adult GBM self-renewing cells•MLL5 favors self-renewal and H3.3 favors differentiation in adult GBM•An MLL5/H3.3 signature predicted two compounds that curb GBM self-renewal
Gallo et al. show that MLL5 induces reorganization of chromatin structure and decreases expression of H3.3. Reduced H3.3 expression favors self-renewal properties of adult glioblastoma (GBM) cells and phenocopies pediatric GBM with H3.3 mutations, indicating potential therapeutic strategies for adult GBM.