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Inhibition of H3K27M-enhanced ATM signaling increases radiation efficacy in diffuse midline glioma

ABSTRACT: H3K27-altered diffuse midline glioma (DMG) is an aggressive and treatment-resistant form of pediatric high-grade glioma (pHGG). The disease is defined by point mutations in histone H3 that convert lysine 27 to methionine (termed H3K27M), resulting in genome-wide epigenetic changes that drive tumorigenesis. While radiation therapy is the standard of care, subsequent recurrence, often within the high dose radiation field, is universal. We found that the apical DNA damage response kinase Ataxia Telangiectasia-Mutated (ATM) was uniquely upregulated in H3K27M-expressing patient tumor samples compared to pHGG expressing only wild type histone H3. Using a panel of H3K27 isogenic cell lines, we further found that H3K27M was associated with reduced H3K27me3 within the ATM promoter, increased ATM mRNA levels, and elevated DNA damage response (DDR) signaling, even in the absence of radiation-induced DNA damage. In assessing the effect of these changes on the ability of AZD1390, a clinical-grade, CNS-penetrant ATM inhibitor, to sensitize cells to radiation, we found that while exogenous expression of H3K27M conferred preferential radiosensitization by AZD1390, CRISPR/Cas9 deletion of H3K27M did not attenuate the efficacy of AZD1390 in patient derived DMG cell lines. Finally, AZD1390 sensitized orthotopic H3K27M mutant tumors to radiotherapy in both immune deficient and syngeneic immune competent hosts with minimal adverse effects. Taken together, these data provide a direct mechanistic link between the H3K27M mutation and ATM expression and support the recently initiated clinical investigation of AZD1390 with radiotherapy in newly diagnosed pHGG.

ORGANISM(S): Mus musculus

PROVIDER: GSE337340 | GEO | 2026/07/09

REPOSITORIES: GEO

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