TMET-27. Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis

Abstract Isocitrate dehydrogenase (IDH) gene mutations occur early among the genetic alterations that lead to the formation of lower-grade adult-type diffuse gliomas. Mutant IDH enzymes synthesize the oncometabolite (R)-2-hydroxyglutarate (2HG), which inhibits α-ketoglutarate-dependent dioxygenases, including those involved in DNA and histonedemethylation. Although this epigenetic dysregulation is thought to play a central role in gliomagenesis, the precise mechanisms linking mutant IDH to glioma initiation remain incompletely understood. To address this, we developed a genetically engineered mouse model of astrocytoma driven by the IDH1-R132H oncogene and performed time-resolved single-cell RNA and ATAC sequencing to capture the molecular and cellular dynamics of early glioma development. We found that mutant IDH activates neural progenitor cells (NPCs) and shifts their lineage priming toward a glial, as opposed to a neuronal, fate. Together, these effects caused expansion of oligodendrocyte precursor cells (OPCs) and depletion of interneurons and neuroblasts. Importantly, we observed that the malignant clone that drives glioma initiation preferentially arises among OPCs, but not neuronal cells. Our findings provide direct evidence that OPCs are the dominant cell type of origin for IDH-mutant gliomas, corroborating prior evidence for this idea based on comparative gene expression profiling and other approaches. Mechanistically, NPC fate reprogramming was associated with promoter hypermethylation and transcriptional silencing of Gsx2, a homeobox transcription factor essential for interneuron specification. Ablating Gsx2 in IDH-wildtype NPCs recapitulated mutant IDH-induced lineage switching and OPC expansion, indicating that Gsx2 repression is a key consequence of mutant IDH activity during glioma initiation. Our findings define a developmental and epigenetic mechanism through which IDH mutations rewire NPC fate to favor glioma-permissive lineages. By linking metabolic signaling to chromatin remodeling and altered cell fate specification, our study provides insight into how IDH mutations exploit neurodevelopmental programs to promote gliomagenesis.