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Article: Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas

TitleMutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas
Authors
KeywordsPIK3CA
E6201
ACVR1
HIST1H3B
diffuse intrinsic pontine glioma
brain cancer
bone morphogenetic protein
cancer therapeutic
glioma
oligodendrocyte
Issue Date2020
Citation
Cancer Cell, 2020, v. 37, n. 3, p. 308-323.e12 How to Cite?
AbstractDiffuse 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 Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V 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.
Persistent Identifierhttp://hdl.handle.net/10722/292148
ISSN
2023 Impact Factor: 48.8
2023 SCImago Journal Rankings: 17.507
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorFortin, Jerome-
dc.contributor.authorTian, Ruxiao-
dc.contributor.authorZarrabi, Ida-
dc.contributor.authorHill, Graham-
dc.contributor.authorWilliams, Eleanor-
dc.contributor.authorSanchez-Duffhues, Gonzalo-
dc.contributor.authorThorikay, Midory-
dc.contributor.authorRamachandran, Parameswaran-
dc.contributor.authorSiddaway, Robert-
dc.contributor.authorWong, Jong Fu-
dc.contributor.authorWu, Annette-
dc.contributor.authorApuzzo, Lorraine N.-
dc.contributor.authorHaight, Jillian-
dc.contributor.authorYou-Ten, Annick-
dc.contributor.authorSnow, Bryan E.-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorGoldhamer, David J.-
dc.contributor.authorSchramek, Daniel-
dc.contributor.authorBullock, Alex N.-
dc.contributor.authorDijke, Peter ten-
dc.contributor.authorHawkins, Cynthia-
dc.contributor.authorMak, Tak W.-
dc.date.accessioned2020-11-17T14:55:52Z-
dc.date.available2020-11-17T14:55:52Z-
dc.date.issued2020-
dc.identifier.citationCancer Cell, 2020, v. 37, n. 3, p. 308-323.e12-
dc.identifier.issn1535-6108-
dc.identifier.urihttp://hdl.handle.net/10722/292148-
dc.description.abstractDiffuse 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 Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V 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.-
dc.languageeng-
dc.relation.ispartofCancer Cell-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectPIK3CA-
dc.subjectE6201-
dc.subjectACVR1-
dc.subjectHIST1H3B-
dc.subjectdiffuse intrinsic pontine glioma-
dc.subjectbrain cancer-
dc.subjectbone morphogenetic protein-
dc.subjectcancer therapeutic-
dc.subjectglioma-
dc.subjectoligodendrocyte-
dc.titleMutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.ccell.2020.02.002-
dc.identifier.pmid32142668-
dc.identifier.pmcidPMC7105820-
dc.identifier.scopuseid_2-s2.0-85081204106-
dc.identifier.volume37-
dc.identifier.issue3-
dc.identifier.spage308-
dc.identifier.epage323.e12-
dc.identifier.eissn1878-3686-
dc.identifier.isiWOS:000520110400007-
dc.identifier.issnl1535-6108-

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