ATRX loss in glioma results in epigenetic dysregulation of cell cycle phase transition [scRNA-seq]

ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and IDH-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We found that ATRX binds regulatory elements of cell cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell cycle regulator ATM with irradiation. Mice intra-cranially implanted with ATRX-deficient GBM cells demonstrate doubling of median survival compared to the ATRX-Wild Type controls when treated with ATM inhibitor AZD0156 and radiation. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display epigenetic dysregulation of cell cycle phase transitions, which opens a new window for therapies targeting this unique phenotype. Overall design: scRNA-seq data comparison between one ATRX-KO U251 sample and one ATRX-WT U251 sample