ATRX loss promotes gliomagenesis by converged actions on neural differentiation and telomere maintenance

The chromatin remodeler ATRX is frequently mutated or depleted in a range of human malignancies, including pediatric and adult gliomas, yet the mechanism underlying its tumor suppressor function remains unclear. Here we combine primary murine and human neural stem/progenitor cell (NSC)-based systems to demonstrate that ATRX modulates glioma pathogenesis through two independent and convergent functions. Firstly, we show that ATRX regulates neural development by facilitating neuronal maturation. Depletion of ATRX blocks neural differentiation and promotes gliomagenesis. Concurrently, we show that ATRX is required for efficient telomere DNA replication in human but not murine NSCs, since Pot1b binding to telomeric G-rich single-strand DNA suppresses Atrx deletion-induced telomere defects in mouse cells. Loss of ATRX in human NSCs destabilizes telomere homeostasis, which triggers a robust DNA damage response (ATR-CHK1/CHK2 pathway) and induces ALT-like phenotypes that initially limit mutant cell proliferation. Only a small fraction (approximately 1-3%) of ATRX-null human NSCs stably activate ALT to escape growth restriction, consistent with the indolent clinical progression of human ATRX-mutant gliomas. These findings support a hypothetical three-step model that reconciles the initial indolence and eventual malignant progression of ATRX-deficient gliomas. Our study clarifies species-specific differences in ATRX function and has important mechanistic and clinical implications for the development of targeted therapies for ATRX-mutant gliomas.