Abstract A46: Heterotypic nucleosomes and PRC2 role in diffuse intrinsic pontine gliomas

Abstract

Abstract Diffuse intrinsic pontine gliomas (DIPG) harbor a characteristic lysine-to-methionine mutation on histone H3 (H3K27M) that potently inhibits Polycomb Repressive Complex 2 (PRC2) enzymatic activity; however, the precise roles of H3K27M and PRC2 in tumorigenesis remain elusive. Here we perform epigenomic profiling of patient-derived H3K27M mutant DIPG cell lines and demonstrate that H3K27M resides in nucleosomes with H3K27acetylation (H3K27ac) and colocalizes with bromodomain proteins at actively transcribed genes. In contrast, PRC2 is excluded from H3K27M occupied regions but, strikingly, the PRC2 complex is required for maintaining oncogenic potential. Finally, we demonstrate that pharmacologic bromodomain inhibition suppresses tumor growth in vivo. Altogether our results indicate that H3K27M drives accumulation of H3K27ac and point to bromodomain proteins inhibition as a powerful clinical strategy against DIPG. Citation Format: Andrea Piunti. Heterotypic nucleosomes and PRC2 role in diffuse intrinsic pontine gliomas [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A46.