SRA

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. Overall design: Fresh or frozen IDH-mutant gliomas treated with IDHi were dissociated and profiled by single-cell or single-nucleus RNA sequencing (Smart-seq2 or 10x). In-vitro IDH-mutant glioma models treated with or without IDHi was profiled by single-cell RNA-seq (10x) and single-cell multi-omics protocol (DNA methylome and transcriptome). In-vitro IDH-mutant glioma models that we knock out Notch1 (Notch1-KO) and the control (Notch1-WT) were profiled by single-cell RNA-sequencing (10x).