Author:
Mangoli Avani,Wu Sophie,Liu Harrison Q.,Aksu Michael,Jain Vaibhav,Foreman Bronwen E.,Regal Joshua A.,Weidenhammer Loren B.,Stewart Connor E.,Guerra Garcia Maria E.,Hocke Emily,Abramson Karen,Williams Nerissa T.,Luo Lixia,Deland Katherine,Attardi Laura,Abe Kouki,Hashizume Rintaro,Ashley David M.,Becher Oren J.,Kirsch David G.,Gregory Simon G.,Reitman Zachary J.
Abstract
SummaryDiffuse 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 nativeH3f3aallele 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 spatialin situtranscriptomics 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.
Publisher
Cold Spring Harbor Laboratory