Abstract
In utero expression of H3.3K27M with Trp53 loss in mice recapitulates human pediatric high-grade glioma.
Major finding: In utero expression of H3.3K27M with Trp53 loss in mice recapitulates human pediatric high-grade glioma.
Concept: H3.3K27M mutations induce tumorigenesis only during a specific window of mouse development.
Impact: The H3.3K27M-driven glioma mouse model may facilitate the identification of targetable vulnerabilities.
Gain-of-function mutations in the histone variant H3.3 (including H3.3K27M) occur frequently in patients with pediatric high-grade glioma and are often accompanied by loss of TP53 and amplification of PDGFRA. H3.3K27M functions as an “oncohistone” and suppresses polycomb repressive complex 2 (PRC2) activity to reduce trimethylation of histone 3 at lysine 27 (H3K27me3) and support tumorigenesis. However, models to study the function of H3.3K27M in vivo are lacking. Pathania and colleagues developed a mouse model of pediatric high-grade glioma carrying the H3.3K27M mutation and Trp53 loss. The H3.3K27M mutation along with Trp53 loss in the hindbrain or the forebrain was sufficient to induce tumorigenesis in utero. However, postnatal expression of H3.3K27M with Trp53 loss or delivery to the entire stem cell pool did not lead to tumorigenesis. The H3.3K27M-driven tumors recapitulated many of the features of human pediatric high-grade glioma including diffuse spreading, rapid proliferation, H3K27me3 depletion, and OLIG2 expression. H3.3K27M mutations are often accompanied by mutations in ATRX, and ATRX loss combined with H3.3K27M expression and Trp53 loss resulted in more circumscribed tumors. In contrast, PDGFRA overexpression accelerated tumorigenesis, resulting in increased tumor invasion. Screening of a small-molecule kinase inhibitor library in H3.3K27M tumor cells identified several vulnerabilities previously linked to pediatric high-grade glioma, suggesting that this model may allow for the identification of targeted therapies. Altogether, this mouse model of pediatric high-grade glioma suggests that tumorigenesis occurs only when H3.3K27M is introduced during a specific window during mouse brain development and may allow for the identification of targetable dependencies in these tumors.
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