H3.3K27M cooperates with p53 loss and Pdgfra gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas [Mouse WES]

Gain-of-function mutations in histone 3 (H3) variants are found in a large proportion ofpediatric 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 whole-exome sequencing (WES) of 10 spatial biopsies of a K27M-AP tumor (H3.3K27M, Trp53-/- and Atrx shRNA). We employed in utero electroporation and a piggyBac transposon-based system to deliver mutant H3.3K27M, Atrx shRNA and Trp53 CRISPR/Cas9 into developing NPCs – and all their successive progeny – during embryonic neurogenesis in vivo.