Cooperativity between H3.3K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars.

ABSTRACT: Diffuse midline glioma (DMG) is a leading cause of brain tumor death in children. In addition to hallmark H3.3K27M mutations, significant subsets also harbor alterations of other genes, such as TP53 and PDGFRA. Despite the prevalence of H3.3K27M, the results of clinical trials in DMG have been mixed, possibly due to the lack of models recapitulating its genetic heterogeneity. To address this gap, we developed human iPSC-derived tumor models harboring TP53^R248Q with or without heterozygous H3.3K27M and/or PDGFRA^D842V overexpression. The combination of H3.3K27M and PDGFRA^D842V resulted in more proliferative tumors when gene-edited neural progenitor (NP) cells were implanted into mouse brains compared to NP with either mutation alone. Transcripto

SUBMITTER: Skinner KR 

PROVIDER: S-EPMC9980117 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature