MLL5 Promotes Self-Renewing Glioblastoma Growth via H3.3 Suppression

A large portion of pediatric glioblastomas (GBM) harbor mutations in the histone 3 variant H3.3 (encoded by H3F3A and H3F3B), which is replication-independent and associated with active chromatin. However, H3.3 mutations are rarely found in adult patients. In order to identify mutation-independent alterations in histone biology in adult GBM, Gallo and colleagues analyzed GBM DNA methylation profiles. Adult GBM self-renewing cells clustered with pediatric samples, and adult GBM cultures had reduced levels of H3.3, suggesting that epigenetic mechanisms may disrupt H3.3 in adult GBM self-renewing cells. Gene expression profiling identified mixed lineage leukemia 5 (MLL5, also known as KMT2E) as highly expressed in GBM and a putative regulator of H3.3. Expression of H3F3B, but not H3F3A, was inversely correlated with MLL5 expression, and MLL5 overexpression resulted in more compact chromatin at the H3F3B transcription start site, suggesting that MLL5 reduced H3F3B expression through chromatin alterations. In addition, MLL5 induced a global reduction in the activating mark histone H3 lysine 4 trimethylation and increased local chromatin condensation. Increased expression of H3.3 was associated with GBM differentiation, whereas MLL5 promoted self-renewal, supporting the idea that MLL5 enhances GBM cell self-renewal by decreasing H3.3 expression. In vivo, overexpression of MLL5 in an orthotopic mouse model of GBM increased tumor formation, and adult patients with high levels of H3.3 had better outcomes than patients with lower expression. Small-molecule inhibitors targeting the epigenetic regulators multiple endocrine neoplasia 1 and lysine (K)-specific demethylase 6B, which are coregulated with MLL5, reduced the self-renewing capacity of GBM cells. These findings indicate that MLL5 promotes GBM tumorigenesis and self-renewal by reducing H3.3 expression and reorganizing chromatin. This represents an epigenetic mechanism that phenocopies pediatric GBM driven by H3.3 mutations, and suggests that targeting epigenetic regulators may be effective in adult GBM.

Gallo M, Coutinho FJ, Vanner RJ, Gayden T, Mack SC, Murison A, et al. MLL5 orchestrates a cancer self-renewal state by repressing the histone variant H3.3 and globally reorganizing chromatin. Cancer Cell 2015;28:715–29.

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