Abstract IA12: Investigating the functional consequences of ATRX deficiency in glioma

Abstract

Abstract Comprehensive genomic profiling in cancer continues to reveal frequent alterations in epigenetic regulators, firmly implicating chromatin biology in the oncogenic process. We and others recently found that inactivating mutations in the SWI/SNF family member ATRX represent defining molecular alterations in diffusely infiltrating gliomas, where they invariably pair with mutations in TP53 and IDH1/2. ATRX normally regulates the composition of histone monomers at a variety of sites across the genome, and may also affect the distribution of specific histone modifying complexes. A number of studies have linked ATRX deficiency to a wide spectrum of physiological dysfunction, including aberrant gene regulation, abnormal telomere maintenance, genomic instability, and aneuploidy. Nevertheless, the precise mechanisms by which ATRX deficiency promotes oncogenesis remain unknown. To investigate the effects of ATRX deficiency on chromatin structure, gene expression, and transformation, we inactivated Atrx in murine neuroepithelial progenitor cells (NPCs) also lacking Tp53. We found that, in this context, Atrx deficiency induced widespread alterations in chromatin accessibility and organization, which in turn led to dramatic shifts in gene expression. Among the altered transcriptional networks were pathways implicated in cellular motility and invasion, an established feature of diffusely infiltrating gliomas. Intriguingly, Atrx-deficient NPCs also exhibited significantly increased transwell migration. Our findings demonstrate that ATRX deficiency promotes disease-relevant biological behavior by modulating chromatin accessibility and influencing gene expression. We are now performing detailed epigenetic and biochemical studies to identify the precise transcriptional events mediating these effects. We are also investigating how IDH mutations influence the genomic distribution of ATRX, thereby modulating its function and the consequences of its deficiency. Citation Format: Jason T. Huse. Investigating the functional consequences of ATRX deficiency in glioma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA12.