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

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.