Investigating the Tumorigenesis Mechanisms and Vulnerabilities of Pediatric High-grade Gliomas with H3G34R/V

Pediatric high-grade gliomas (pHGGs) is a deadly disease that requires robust research to develop effective therapies. Recently, recurring mutations in genes encoding histone H3 have been identified in pHGGs, including H3K27M and H3G34R/V. Histones are the proteins that pack DNA together and influences caused by such mutations outside of DNA are considered epigenetic changes. Pediatric HGGs with these mutations show distinct gene expression patterns and epigenetic landscapes, suggesting that the mechanisms of tumor growth might be different and they might require different therapeutic strategies. Pediatric HGGs with H3G34R/V, which is less well-studied than pHGGs with H3K27M, will be the major focus of this study. The goals of this project are to identify direct genomic targets of H3G34R/V in pHGG cell lines. This study could reveal previously unknown tumorigenesis mechanisms and novel drug targets of H3G34R/V pHGGs. Cell lines derived from different H3G34R/V pHGG patients have different genetic backgrounds, therefore findings in one specific cell line may not apply to others. To find mechanisms and drug targets that apply to most patients with H3G34R/V, it is critical to perform experiments in multiple H3G34R/V pHGG cell lines and identify the common mechanisms and potential therapeutic targets. This is why the Children’s Brain Tumor Network’s contribution of preclinical models to this project is so important.