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Mutant IDH inhibitors induce lineage differentiation in IDH-mutant Oligodendroglioma III

GSE260997 Mus musculus; Homo sapiens Expression profiling by high throughput sequencing 2458 samples Submitted 2024/05/01 Platform GPL30172Platform GPL30173
Summary
A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation towards the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.
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Also filed as BioProject PRJNA1084806 and SRA study SRP493670. Searching any of these in the dataset finder brings you back here.

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