Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.

• MeSH
• Astrocytes metabolism   pathology   MeSH
• Models, Biological MeSH
• Cell Lineage MeSH
• Chromatin metabolism   MeSH
• Embryo, Mammalian metabolism   MeSH
• Epigenesis, Genetic MeSH
• Transcription, Genetic MeSH
• Glioma genetics   pathology   MeSH
• Histones genetics   metabolism   MeSH
• Interneurons metabolism   MeSH
• Carcinogenesis genetics   pathology   MeSH
• Lysine metabolism   MeSH
• Mutation genetics   MeSH
• Mice, Inbred C57BL MeSH
• Brain Neoplasms genetics   pathology   MeSH
• Neural Stem Cells metabolism   MeSH
• Oligodendroglia metabolism   MeSH
• Prosencephalon embryology   MeSH
• Cellular Reprogramming genetics   MeSH
• Promoter Regions, Genetic genetics   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Receptor, Platelet-Derived Growth Factor alpha genetics   metabolism   MeSH
• Neoplasm Grading MeSH
• Transcriptome genetics   MeSH
• Gene Silencing MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH