H3.3^K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas.

ABSTRACT: Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3^K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3^K27M-driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3^K27M-tumor cells serially engraft

SUBMITTER: Pathania M 

PROVIDER: S-EPMC5687892 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature