High-grade
gliomas represent the most lethal class of pediatric
tumors, and their resistance to both radio- and
chemotherapy is associated with a poor prognosis. Recurrent mutations affecting
histone genes drive the
tumorigenesis of some pediatric high-grade
gliomas, and H3K27M mutations are notably characteristic of a subtype of
gliomas called DMG (Diffuse Midline
Gliomas). This dominant negative mutation impairs H3K27 trimethylation, leading to profound epigenetic modifications of genes expression. Even though this mutation was described as a driver event in
tumorigenesis, its role in
tumor cell resistance to treatments has not been deciphered so far. To tackle this issue, we expressed the H3.3K27M mutated
histone in three initially H3K27-unmutated pediatric
glioma cell lines, Res259, SF188, and KNS42. First, we validated these new H3.3K27M-expressing models at the molecular level and showed that K27M expression is associated with pleiotropic effects on the transcriptomic signature, largely dependent on cell context. We observed that the mutation triggered an increase in cell growth in Res259 and SF188 cells, associated with higher clonogenic capacities. Interestingly, we evidenced that the mutation confers an increased resistance to ionizing radiations in Res259 and KNS42 cells. Moreover, we showed that H3.3K27M mutation impacts the sensitivity of Res259 cells to specific drugs among a library of 80 anticancerous compounds. Altogether, these data highlight that, beyond its tumorigenic role, H3.3K27M mutation is strongly involved in pediatric
glioma cells' resistance to
therapies, likely through transcriptomic reprogramming.