Abstract B01: Biological consequences of histone mutations in the mammalian brain

Abstract

Abstract Pediatric high-grade gliomas (HGGs) are devastating diseases with poor prognosis. The two-year survival for pediatric HGG ranges from 30%, for tumors arising in the cerebral cortex, to less than 10% for diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem. Recurrent somatic mutations in histone H3 found in pediatric HGGs are rare in adult HGGs and may represent genetic drivers of disease. Mutually exclusive somatic heterozygous H3F3A or HIST1H3B mutations encoding a K27M variant of histone H3.3 or H3.1, respectively, are found in nearly 80 percent of DIPGs and 22 percent of non-brainstem HGG, where they occur predominantly in thalamic and other midline tumors. Strikingly, heterozygous H3F3A mutations encoding histone H3.3 G34R or G34V occur in approximately 14 percent of non-brainstem HGG, and are associated predominantly with cortical tumors arising in older children through young adulthood, suggesting a distinct developmental origin compared to the majority of tumors harboring K27M mutations. DNA methylation signatures and gene expression patterns distinguish G34R/V and K27M tumors, but the oncogenic mechanisms and brain region selectivity of these mutations are still uncertain. To study these mutations in the developing mammalian brain, we generated conditionally activated, epitope tagged H3f3a knock-in mice to express K27M, G34R or non-mutated H3.3 proteins. When activated in neural and glial precursor cells, extensive H3f3a expression was observed throughout the embryonic brain, and H3.3-K27M induced loss of H3K27me3, consistent with observations in K27M mutant DIPG tumor samples. Moreover, neural stem cells expressing H3.3-K27M demonstrated an in vitro growth advantage compared to H3.3-G34R or H3.3-WT expressing neural stem cells. We will present an analysis of the epigenetic landscape and gene expression signatures associated with the histone H3 K27M and G34R mutations in different brain regions as well as phenotypic analysis of the mutant mice. Citation Format: Jon D. Larson, Lawryn H. Kasper, Helen R. Russell, Chunxu Qu, Xiaoyan Zhu, Peter J. McKinnon, Suzanne J. Baker. Biological consequences of histone mutations in the mammalian brain. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B01.