| First Author | Pathania M | Year | 2017 |
| Journal | Cancer Cell | Volume | 32 |
| Issue | 5 | Pages | 684-700.e9 |
| PubMed ID | 29107533 | Mgi Jnum | J:249297 |
| Mgi Id | MGI:6093866 | Doi | 10.1016/j.ccell.2017.09.014 |
| Citation | Pathania M, et al. (2017) H3.3(K27M) Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas. Cancer Cell 32(5):684-700.e9 |
| abstractText | 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. |
