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 toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in 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.

中文翻译：

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突变 IDH 抑制剂诱导 IDH 突变少突胶质细胞瘤谱系分化

一部分 IDH 突变神经胶质瘤患者对突变 IDH (IDHi) 抑制剂有反应，但这种反应的分子基础尚不清楚。在这里，我们通过单细胞或单核 RNA 测序对来自 IDHi 临床获益患者的三种 IDH 突变少突胶质细胞瘤进行了分析。重要的是，在治疗开始后四个星期后，在用药期间对组织进行取样。我们进一步将我们的发现与来自独立队列和实验模型的单细胞和批量转录组的分析相结合。我们发现 IDHi 治疗可诱导向星形胶质细胞谱系的强烈分化，并伴有干细胞样细胞的消耗和细胞增殖的减少。此外，突变与星形胶质细胞分化减少有关，并可能限制对 IDHi 的反应。我们的研究强调了 IDHi 对驱动少突神经胶质瘤的细胞层次结构的分化潜力，并提出了一种可以改善患者分层的遗传修饰剂。