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H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas.
Cancer Cell ( IF 50.3 ) Pub Date : 2017-11-13 , DOI: 10.1016/j.ccell.2017.09.014
Manav Pathania 1 , Nicolas De Jay 2 , Nicola Maestro 1 , Ashot S Harutyunyan 2 , Justyna Nitarska 3 , Pirasteh Pahlavan 4 , Stephen Henderson 5 , Leonie G Mikael 2 , Angela Richard-Londt 6 , Ying Zhang 6 , Joana R Costa 3 , Steven Hébert 7 , Sima Khazaei 2 , Nisreen Samir Ibrahim 2 , Javier Herrero 5 , Antonella Riccio 3 , Steffen Albrecht 8 , Robin Ketteler 3 , Sebastian Brandner 6 , Claudia L Kleinman 9 , Nada Jabado 10 , Paolo Salomoni 11
Affiliation  

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.

中文翻译:

H3.3K27M 与小鼠胚胎神经祖细胞中的 Trp53 缺失和 PDGFRA 增加协同诱导侵袭性高级胶质瘤。

在很大一部分儿科高级别胶质瘤 (pHGG) 中发现了组蛋白 3 (H3) 变体的功能获得性突变,通常与 TP53 丢失和血小板衍生生长因子受体 α (PDGFRA) 扩增有关。在这里,我们描述了一种体细胞小鼠模型,其中如果在子宫内引入,仅 H3.3 K27M和 Trp53 损失就足以进行肿瘤转化。H3.3 K27M驱动的病变是克隆性的、H3K27me3 耗尽、Olig2 阳性、高度增殖和扩散扩散,因此概括了 pHGG 的标志性分子和组织病理学特征。添加野生型 PDGFRA 可减少潜伏期并增加肿瘤侵袭,而 ATRX 敲低与更多局限的肿瘤相关。H3.3 K27M- 肿瘤细胞连续植入受体小鼠,初步药物筛选揭示了突变特异性脆弱性。总体而言,我们提供了一个忠实的 H3.3 K27M -pHGG 模型,可以深入了解癌组蛋白的发病机制和研究未来的治疗方法。
更新日期:2017-10-27
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