Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.
Cancer Cell
; 42(5): 904-914.e9, 2024 May 13.
Article
en En
| MEDLINE
| ID: mdl-38579724
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Oligodendroglioma
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Neoplasias Encefálicas
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Diferenciación Celular
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Isocitrato Deshidrogenasa
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Mutación
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Cell
Asunto de la revista:
NEOPLASIAS
Año:
2024
Tipo del documento:
Article
País de afiliación:
Israel