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Ataxia-telangiectasia mutated kinase disruption enhances the efficacy of radiation therapy in spatially-directed diffuse midline gliomas

ABSTRACT: Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by p53-inactivating mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress. Using RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce native H3.3K27M mutations in a lineage- and spatially-directed manner, we generated primary mouse tumors that recapitulate human DMG. Disrupting ataxia-telangiectasia mutated kinase (ATM) enhanced the efficacy of radiation therapy in murine and patient-derived DMG models, increasing survival. Microscopy-based in situ sequencing was used to spatially resolve transcriptional profiles in >750,000 single cells with or without ATM disruption and radiation therapy, revealing altered immune-neoplastic and endothelial cell interactions after treatment. An allelic series of primary murine DMG models with different p53 mutations confirmed that transactivation-independent p53 activity is a key mediator of radiosensitivity after ATM disruption. Our findings contribute primary DMG mouse models with deep profiling and reveal the mechanisms of treatment response to an actionable therapeutic strategy.

ORGANISM(S): Mus musculus

PROVIDER: GSE284759 | GEO | 2025/06/16

REPOSITORIES: GEO

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Ataxia-telangiectasia mutated (Atm) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas to radiation therapy

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