Abstract Diffuse midline gliomas (DMG) are among the deadliest pediatric and adult brain tumors with a grim median survival of less than 2 years. The tumor’s eloquent location within the brain and aggressive nature emphasizes the need for new therapeutic approaches. Approximately 10% of DMGs harbor activating, truncating mutations in protein phosphatase magnesium-dependent 1D (PPM1D), a crucial protein in the DNA damage response pathway. Currently, no mouse alleles exist that allow for tissue-specific expression of epitope-tagged, truncated PPM1D from the endogenous Ppm1d locus to model DMGs. We have developed a novel model that utilizes the RCAS/TV-a and loxP systems to conditionally express truncated PPM1D with a 3x Myc tag in neural stem cells to stimulate DMG growth. Using the model, we have confirmed the oncogenic properties of PPM1D using in vivo survival studies, which show decreased tumor-free survival in comparison to wildtype controls. However, we show that the pro-tumor effects of mutant PPM1D do not drive tumorigenesis as strongly as total p53 loss. We show accelerated growth in vitro using mouse embryonic fibroblastas (MEFs) and upregulation of cell cycle pathways as demonstrated by single-cell RNA sequencing data. Additionally, we show that truncated PPM1D radiosensitizes MEFs, possibly due to impaired DNA repair and ROS scavenging. We also confirm the downstream impact of truncated PPM1D on DNA damage response proteins following in vitro treatment with ionizing radiation (IR). These results suggest our autochthonous model offers a faithful representation of DMG and insights into therapeutics for DMGs harboring PPM1D mutations.
Groth et al. (Fri,) studied this question.