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Mutant ACVR1 arrests glial cell differentiation to drive tumorigenesis in pediatric gliomas

DOI: 10.1016/j.ccell.2020.02.002 DOI Help

Authors: Jerome Fortin (University Health Network, Toronto) , Ruxiao Tian (University Health Network, Toronto) , Ida Zarrabi (University Health Network, Toronto) , Graham Hill (University Health Network, Toronto) , Eleanor Williams (Structural Genomics Consortium, University of Oxford) , Gonzalo Sanchez-duffhues (Leiden University Medical Center) , Midory Thorikay (Leiden University Medical Center) , Parameswaran Ramachandran (University Health Network, Toronto) , Robert Siddaway (The Hospital for Sick Children, Canada) , Jong Fu Wong (Structural Genomics Consortium, University of Oxford) , Annette Wu (University Health Network, Toronto) , Lorraine N. Apuzzo (University of Connecticut) , Jillian Haight (University Health Network, Toronto) , Annick You-ten (University Health Network, Toronto) , Bryan E. Snow (University Health Network, Toronto) , Andrew Wakeham (University Health Network, Toronto) , David J. Goldhamer (University of Connecticut) , Daniel Schramek (Mount Sinai Hospital, Canada) , Alex N. Bullock (Structural Genomics Consortium, University of Oxford) , Peter Ten Dijke (University Medical Center, Leiden) , Cynthia Hawkins (The Hospital for Sick Children, Canada) , Tak W. Mak (University Health Network, Toronto)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cancer Cell , VOL 37 , PAGES 308 - 323.e12

State: Published (Approved)
Published: March 2020
Diamond Proposal Number(s): 15433

Abstract: Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1 G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3b K27M and Pik3ca H1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1 G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.

Journal Keywords: diffuse intrinsic pontine glioma; brain cancer; glioma; bone morphogenetic protein; PIK3CA; ACVR1; cancer therapeutic; HIST1H3B; E6201; oligodendrocyte

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

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