Abstract 1118: DOT1L epigenetically regulates cancer stem cell properties and tumor progression in glioblastoma brain tumor stem cells

Abstract

Abstract The median survival for patients diagnosed with Glioblastoma (GBM) is only 14 months, due to recurrence, despite current treatment options of surgery, radio- and chemo-therapies. Brain tumor stem cells (BTSCs) are thought to underlie disease recurrence and lethality as they exhibit self-renewal, multipotency and tumorigenesis. The epigenetic regulation of BTSCs are relatively un-characterized and unlike genomic mutations are potentially reversible. Disrupter of telomeric silencing-1-like (DOT1L) is the only known histone methyltransferase responsible for histone-3-lysine-79 methylation (H3K79me), an epigenetic mark associated with active gene transcription. Previous studies investigating the therapeutic implications of targeting DOT1L in cancer have shown that its inhibition in leukemia results in cancer cell death and, in solid cancers, decreases metastasis. We investigated the role of DOT1L in GBM BTSCs. We find that short-term DOT1L inhibition in BTSCs in vitro has limited effects on viability but alters growth morphology, as neurospheres become flattened and adherent. Furthermore, inhibition decreases BTSC invasion and promotes differentiation. Long-term inhibition of DOT1L had a more pronounced effect on sphere morphology and decreased BTSC proliferation and survival. Pre-treatment with the DOT1L inhibitor EPZ-5676 followed by orthotopic xenografts of BTSCs led to slowed tumor growth and improved overall survival. Initial H3K79me2 ChIP-sequencing and RNA-sequencing results show that H3K79me2 levels and gene expression are decreased for stem and progenitor cell markers SOX2 and OLIG2 respectively, in BTSCs treated with EPZ-5676. These results suggest that DOT1L may be an important regulator of GBM cancer stem cell properties and tumor progression. Current studies aim to further investigate how DOT1L regulates BTSCs by overlaying H3K79me2 ChIP-sequencing, RNA-sequencing and ATAC-sequencing in a panel of BTSCs following DOT1L inhibition and overexpression. These findings highlight the potential clinical implications of epigenetic targeted therapies for GBM. Citation Format: Danielle Bozek, Xiaoguang Hao, H. Artee Luchman, Samuel Weiss. DOT1L epigenetically regulates cancer stem cell properties and tumor progression in glioblastoma brain tumor stem cells [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 1118.