Abstract

Abstract Comprehensive genomic profiling in cancer continues to reveal frequent alterations in epigenetic regulators, firmly implicating chromatin biology in the oncogenic process. For instance, genetic inactivation of the SWI/SNF chromatin regulator ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in both adult and pediatric malignant glioma, and occurs frequently in other cancers as well. ATRX deficiency has been linked to a wide spectrum of physiological dysfunction, including aberrant gene regulation, abnormal telomere maintenance, genomic instability, and aneuploidy. However, the precise oncogenic mechanism(s) induced by ATRX deficiency remain unclear, particularly those involving epigenomic dysregulation. To model these events in putative glioma cells of origin, we inactivated Atrx in primary murine neuroepithelial progenitors (mNPCs). Atrx loss, especially when coupled with Tp53 inactivation, promoted mNPC motility while also modulating differentiation state and potential, effectively recapitulating characteristic disease phenotypes and molecular features. Moreover, these phenotypes correlated with altered gene expression profiles in functionally relevant molecular networks (e.g. cell differentiation and migration). Integrating these transcriptional changes with shifts in chromatin accessibility occurring with Atrx deficiency, along with genome-wide Atrx distribution as determined by ChIP-seq, revealed highly significant spatial correlations between differentially expressed genes, regions of altered chromatin compaction, and genomic sites normally occupied by Atrx. Finally, target genes mediating specific Atrx-deficient phenotypes in vitro exhibited similarly selective misexpression in ATRX-mutant human glioma tissues and cell lines. These findings demonstrate that, in appropriate cellular and molecular contexts, ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes. Citation Format: Carla Danussi, Promita Bose, Pedro Silberman, John S. Van Arnam, Mark Vitucci, Oliver Tang, Adriana Heguy, Timothy A. Chan, Erik P. Sulman, Frederick Lang, Chad J. Creighton, Benjamin Deneen, C Ryan Miller, David J. Picketts, Kasthuri Kannan, Jason T. Huse. Atrx inactivation drives motility and dysregulates differentiation in glioma cells of origin through global epigenomic remodeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4322.

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