ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization

ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (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 find that ATRX binds the 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 the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype. [Display omitted] •ATRX binds regulatory elements of CHEK1 in glioma and glioma precursor cells•ATRX loss is associated with loss of the cell-cycle regulator Chk1•Chk1 loss increases reliance on ATM, an alternate cell-cycle checkpoint modulator•ATM inhibition may sensitize ATRX-deficient gliomas to radiation therapy Qin et al. show that ATRX binds the gene regulatory elements and promotes expression of the cell-cycle regulator of CHEK1 in glioma and glioma precursor cells. ATRX loss in high-grade glioma results in decreased Chk1, dysregulation of cell-cycle checkpoints after radiation, and enhanced radio-sensitization with ATM inhibitors.