1. H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas
- Author
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Nicolas De Jay, Leonie G. Mikael, Steffen Albrecht, Nisreen Samir Ibrahim, Ashot S. Harutyunyan, Robin Ketteler, Javier Herrero, Nada Jabado, Claudia L. Kleinman, Pirasteh Pahlavan, Antonella Riccio, Sebastian Brandner, Angela Richard-Londt, Joana R. Costa, Nicola Maestro, Paolo Salomoni, Manav Pathania, Ying Zhang, Steven Hébert, Sima Khazaei, Stephen Henderson, and Justyna Nitarska
- Subjects
0301 basic medicine ,genetics [Cell Transformation, Neoplastic] ,genetics [Glioma] ,X-linked Nuclear Protein ,Cancer Research ,Receptor, Platelet-Derived Growth Factor alpha ,Somatic cell ,genetics [Tumor Suppressor Protein p53] ,metabolism [Neural Stem Cells] ,PDGFRA ,Biology ,metabolism [Glioma] ,Histones ,Mice ,03 medical and health sciences ,metabolism [X-linked Nuclear Protein] ,Growth factor receptor ,pathology [Brain] ,metabolism [Embryonic Stem Cells] ,Glioma ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Neoplastic transformation ,ddc:610 ,ATRX ,genetics [X-linked Nuclear Protein] ,metabolism [Receptor, Platelet-Derived Growth Factor alpha] ,genetics [Histones] ,medicine.disease ,Embryonic stem cell ,Neural stem cell ,genetics [Receptor, Platelet-Derived Growth Factor alpha] ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,metabolism [Brain] ,Mutation ,Immunology ,Cancer research ,RNA Interference ,metabolism [Tumor Suppressor Protein p53] ,Neoplasm Grading ,Tumor Suppressor Protein p53 ,pathology [Glioma] - Abstract
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.
- Published
- 2017
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