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

Publication date: Available online 26 October 2017
Source:Cancer Cell
Author(s): Manav Pathania, Nicolas De Jay, Nicola Maestro, Ashot S. Harutyunyan, Justyna Nitarska, Pirasteh Pahlavan, Stephen Henderson, Leonie G. Mikael, Angela Richard-Londt, Ying Zhang, Joana R. Costa, Steven Hébert, Sima Khazaei, Nisreen Samir Ibrahim, Javier Herrero, Antonella Riccio, Steffen Albrecht, Robin Ketteler, Sebastian Brandner, Claudia L. Kleinman, Nada Jabado, Paolo Salomoni
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.

Graphical abstract

Teaser

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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