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Publication Detail
H3.3K27MCooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Pathania M, De Jay N, Maestro N, Harutyunyan AS, Nitarska J, Pahlavan P, Henderson S, Mikael LG, Richard-Londt A, Zhang Y, Costa JR, He bert S, Khazaei S, Ibrahim NS, Herrero J, Riccio A, Albrecht S, Ketteler R, Brandner S, Kleinman CL, Jabado N, Salomoni P
  • Publication date:
    13/11/2017
  • Journal:
    Cancer Cell
  • Status:
    Accepted
  • Print ISSN:
    1535-6108
Abstract
© 2017 Elsevier Inc. Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3 K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3 K27M -driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3 K27M -tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3 K27M -pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies. Pathania et al. create a model of pediatric high-grade glioma with H3.3K27M/Trp53 mutation. Tumors occur only when alterations are introduced during a specific window of mouse development, and levels of PDGFRA and ATRX modulate tumor phenotype. This model enables the identification of mutation-specific vulnerabilities.
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Neurodegenerative Diseases
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Research Department of Cancer Bio
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Research Department of Cancer Bio
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MRC/UCL Lab for Molecular Cell Bio
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MRC/UCL Lab for Molecular Cell Bio
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