3 years ago

H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas

H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas
Ying Zhang, Nada Jabado, Robin Ketteler, Manav Pathania, Nicolas De Jay, Pirasteh Pahlavan, Javier Herrero, Claudia L. Kleinman, Steffen Albrecht, Nisreen Samir Ibrahim, Sima Khazaei, Justyna Nitarska, Nicola Maestro, Paolo Salomoni, Antonella Riccio, Steven Hébert, Stephen Henderson, Angela Richard-Londt, Leonie G. Mikael, Joana R. Costa, Sebastian Brandner, Ashot S. Harutyunyan

Summary

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 H3.3K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3K27M-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. H3.3K27M-tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3K27M-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies.

Publisher URL: http://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30418-X

DOI: 10.1016/j.ccell.2017.09.014

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