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Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis

Xiao, Y.; Shi, D. D.; Guo, L.; Neumann, E.; Levitt, M. M.; Kaphle, P.; Shipman, T.; Li, H.; Cai, F.; Ramirez, D. M. O.; Zacharias, L.; Chen, Z.; Lin, M.; Puliyappadamba, V. T.; Chen, T.; Savani, M. R.; Pena, S.; Wansapura, J.; Mathews, T. P.; Mishra, P.; Kim, Y. J.; Raj, P.; Richardson, T. E.; Xu, J.; Mack, S. C.; Rahme, G. J.; Bernstein, B. E.; DeBerardinis, R. J.; Tirosh, I.; Suva, M. L.; Xu, L.; Abdullah, K. G.; McBrayer, S. K.

2025-08-13 cancer biology
10.1101/2025.08.12.667486 bioRxiv
Show abstract

Isocitrate dehydrogenase (IDH) mutations arise early in gliomas and are associated with a defined neurodevelopmental cancer cell hierarchy. However, how mutant IDH contributes to this hierarchy and whether this interaction promotes gliomagenesis remain unclear. We captured the dynamics of IDH-mutant glioma initiation in genetically engineered mice through time-resolved, single-cell genomics. Mutant IDH activates and induces lineage switching of neural progenitor cells (NPCs). These actions expand oligodendrocyte precursor cells, the predominant cell-of-origin for these tumors, at the expense of interneurons. Lineage switching is mediated by promoter hypermethylation and silencing of Gsx2, a homeobox gene required for neurogenesis. Critically, Gsx2 ablation recapitulates NPC fate reprogramming by mutant IDH. We provide a new model of neural cell fate control by IDH oncogenes and insights into the developmental origins of glioma.

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