{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T19:08:05Z","timestamp":1778958485406,"version":"3.51.4"},"posted":{"date-parts":[[2023,10,20]]},"group-title":"Cancer Biology","reference-count":44,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,10,20]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  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, which presents therapeutic opportunities. We used RCAS\/tv-a retroviruses and Cre recombinase to inactivate p53 and induce K27M in the native\n                  <jats:italic>H3f3a<\/jats:italic>\n                  allele in a lineage- and spatially-directed manner, yielding primary mouse DMGs. Genetic or pharmacologic disruption of the DNA damage response kinase Ataxia-telangiectasia mutated (ATM) enhanced the efficacy of focal brain irradiation, extending mouse survival. This finding suggests that targeting ATM will enhance the efficacy of radiation therapy for p53-mutant DMG but not p53-wildtype DMG. We used spatial\n                  <jats:italic>in situ<\/jats:italic>\n                  transcriptomics and an allelic series of primary murine DMG models with different p53 mutations to identify transactivation-independent p53 activity as a key mediator of such radiosensitivity. These studies deeply profile a genetically faithful and versatile model of a lethal brain tumor to identify resistance mechanisms for a therapeutic strategy currently in clinical trials.\n                <\/jats:p>","DOI":"10.1101\/2023.10.18.562892","type":"posted-content","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T10:00:28Z","timestamp":1697796028000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>Ataxia-telangiectasia mutated<\/i>\n                  (\n                  <i>Atm<\/i>\n                  ) disruption sensitizes spatially-directed H3.3K27M\/TP53 diffuse midline gliomas to radiation therapy"],"prefix":"10.64898","author":[{"given":"Avani","family":"Mangoli","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harrison 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