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Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.
Spitzer, Avishay; Gritsch, Simon; Nomura, Masashi; Jucht, Alexander; Fortin, Jerome; Raviram, Ramya; Weisman, Hannah R; Gonzalez Castro, L Nicolas; Druck, Nicholas; Chanoch-Myers, Rony; Lee, John J Y; Mylvaganam, Ravindra; Lee Servis, Rachel; Fung, Jeremy Man; Lee, Christine K; Nagashima, Hiroaki; Miller, Julie J; Arrillaga-Romany, Isabel; Louis, David N; Wakimoto, Hiroaki; Pisano, Will; Wen, Patrick Y; Mak, Tak W; Sanson, Marc; Touat, Mehdi; Landau, Dan A; Ligon, Keith L; Cahill, Daniel P; Suvà, Mario L; Tirosh, Itay.
Afiliación
  • Spitzer A; Department 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.
  • Gritsch S; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • Nomura M; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Jucht A; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Fortin J; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada.
  • Raviram R; New York Genome Center, New York, NY, USA; Weill Cornell Medicine, New York, NY, USA.
  • Weisman HR; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Gonzalez Castro LN; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, U
  • Druck N; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Chanoch-Myers R; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel.
  • Lee JJY; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Mylvaganam R; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Lee Servis R; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Fung JM; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Lee CK; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Nagashima H; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Miller JJ; Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • Arrillaga-Romany I; Departments of Neurology and Radiation Oncology, Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
  • Louis DN; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Wakimoto H; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Pisano W; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  • Wen PY; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Mak TW; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China; Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
  • Sanson M; Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
  • Touat M; Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • Landau DA; New York Genome Center, New York, NY, USA; Weill Cornell Medicine, New York, NY, USA.
  • Ligon KL; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: keith_ligon@dfci.harvard.edu.
  • Cahill DP; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: cahill@mgh.harvard.edu.
  • Suvà ML; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: suva.mario@mgh.harvard.edu.
  • Tirosh I; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel. Electronic address: itay.tirosh@weizmann.ac.il.
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.
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Texto completo: 1 Colección: 01-internacional Asunto principal: Oligodendroglioma / Neoplasias Encefálicas / Diferenciación Celular / Isocitrato Deshidrogenasa / Mutación Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Israel
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Texto completo: 1 Colección: 01-internacional Asunto principal: Oligodendroglioma / Neoplasias Encefálicas / Diferenciación Celular / Isocitrato Deshidrogenasa / Mutación Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Israel