H3.3K27M cooperates with p53 loss and Pdgfra gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas [Human RNA-Seq]. Homo sapiens

Gain-of-function mutations in histone 3 (H3) variants are found in a large proportion of pediatric high-grade gliomas (pHGG) and are often associated with p53 loss and PDGFRA amplification. However, a lack of faithful models has hampered investigation of disease mechanisms and preclinical development. Here, we describe a somatic mouse model of H3.3K27M-driven HGG, which faithfully recapitulates human H3.3K27M pHGG. H3.3K27M and p53 loss are sufficient for neoplastic transformation but only within a specific window of brain development. In this model, H3.3K27M primes the PDGFRA pathway during transformation, and accordingly gain of wild-type PDGFRA decreases latency and increases invasion. Finally, we reveal a previously underappreciated dynamic regulation of H3K27 trimethylation at specific loci. Overall, this experimental model provides key insights into oncohistone-driven pHGG pathogenesis and will enable investigations of future therapies. Overall design: We performed genome-wide transcriptome profiling (RNAseq) of 12 samples derived from human patients: matched normal brain controls (normal brain tissue from pediatric brain tumor patients; n = 3), pediatric high-grade gliomas (pHGG) that are wild-type for H3.3 and TP53 (n = 4), pHGG with H3.3K27M and loss-of-function TP53 mutations (n = 5).