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Updated: Jun 29, 2025
A Protocol for Explant Cultures of IDH1-mutant Diffuse Low-grade Gliomas
Published on: May 9, 2025
Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma
Avishay Spitzer1, Simon Gritsch2, Masashi Nomura3
1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel; Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Abstract:
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 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.
Insights
Inhibitors of mutant isocitrate dehydrogenase (IDHi) promote glioma cell differentiation, reducing proliferation. NOTCH1 mutations may hinder this response, impacting treatment effectiveness.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Genomics
Background:
- A subset of IDH-mutant glioma patients benefit from IDH inhibitors (IDHi).
- The molecular mechanisms driving IDHi response remain unclear.
- Understanding these mechanisms is crucial for optimizing glioma treatment.
Purpose of the Study:
- To investigate the cellular and molecular effects of IDHi treatment in IDH-mutant oligodendroglioma.
- To identify factors influencing patient response to IDHi therapy.
- To elucidate the role of cellular hierarchy and genetic modifiers in treatment outcomes.
Main Methods:
- Single-cell/single-nucleus RNA sequencing of patient-derived IDH-mutant oligodendrogliomas on IDHi.
- Integration with independent cohort transcriptomic data (single-cell and bulk).
- Analysis of experimental models to validate findings.
Main Results:
- IDHi treatment induced significant astrocytic differentiation.
- A depletion of stem-like cells and reduced cell proliferation were observed.
- NOTCH1 mutations were associated with impaired astrocytic differentiation and potentially limited IDHi response.
Conclusions:
- IDHi therapy demonstrates potent differentiation effects on glioma cellular hierarchies.
- NOTCH1 mutations may serve as a predictive biomarker for IDHi response.
- Targeting cellular differentiation pathways offers therapeutic potential for IDH-mutant gliomas.
