Abstract 912: A novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of PRC2 target genes

Abstract Pediatric High Grade Glioma (pHGG) is a collection of molecularly distinct subtypes with different prognoses depending on the genetic drivers. One particularly aggressive subtype is H3.3G34R mutant gliomas, which are currently incurable and in need of improved therapies. Interestingly, H3.3G34R mutant gliomas commonly harbor TP53mutations, ATRX mutations, and alterations in PDGFRA signaling. The mechanism by which H3.3G34R promotes gliomagenesis is still somewhat unclear and additional models are needed to dissect its role in tumorigenesis. We used the RCAS Tv-a system to model H3.3G34R pHGG in mice. Nestin expressing progenitors in the frontal cortex of Nestin-Tva (Ntva); p53 fl/fl; ATRX fl/fl or Ntva; p53 fl/fl mice were infected with H3.3G34R or H3.3WT, PDGFA, and Cre, and monitored for signs and symptoms of tumor formation. RNAseq analysis and immunophenotype were used to characterize the tumors. We observed that H3.3G34R did not significantly impact tumor latency independent of ATRX status. ATRX loss significantly increased tumor latency independent of H3.3G34R (P < 0.01) from 90 days to 143 days. H&E analysis revealed that the majority of tumors in all groups were high grade and that mice with ATRX loss were more likely to develop low grade tumors though this trend did not reach significance (P = 0.075). Expression of Ki67, GFAP and Olig2 was present in all groups, as shown by Immunophenotypic analysis. RNAseq analysis of murine tumor tissue revealed that ATRX loss in the context of G34R led to significant differential expression of 113 genes (78 upregulated and 35 downregulated) including upregulation of PRC2 target genes including HoxA genes. These findings highlight the cooperation between ATRX loss and H3.3G34R in gliomagenesis. Citation Format: Aalaa Abdallah, Herminio J. Cardona, David J. Picketts, Daniel J. Brat, Xiao-Nan Li, Oren J. Becher. A novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of PRC2 target genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 912.