Abstract 869: Molecular characterization of a pediatric high-grade glioma (pHGG) mouse model harboring the H3.3 G34R mutation

Abstract

Abstract Pediatric high-grade glioma (pHGG) accounts for 8-12% of central nervous system tumors and has a 90% mortality rate. Consequently, novel therapies are needed to advance treatment options and improve survival rates. A means to do this is through designing a mouse model that accurately mirrors pHGG in humans to further study this type of pHGG and design treatment options. We focused on the analysis of pHGG harboring mutations on histone H3.3 at glycine 34 (H3.3 G34R) in combination with ATRX and TP53 mutations. We generated a mouse model for pHGG using the sleeping-beauty transposase system and the delivery of plasmids into the sub-ventricular zone of neonatal mice. This results in the transposon-mediated integration of the genetic lesions into the brain cells, thereby allowing the generation of tumors with the desired molecular alterations. Two groups of mice have been developed; the control group (WT H3.3 group) bears tumors generated with the NRASV12 overexpression and two shRNA that target the Tp53 and Atrx genes. The H3.3 G34R group of mice harbors tumors generated with NRASV12 expression, sh-TP53, sh-ATRX, and H3.3 G34R expression. RNA-sequencing was carried out to analyze the transcriptome signature associated with the H3.3 G34R tumor phenotype. Several genes related to the activation of the immune response were differentially upregulated in the H3.3 G34R tumors, such as Ciita, CD74, and Irfl, amongst others. Some of these deregulated genes were validated by immunohistochemistry. Understanding the tumor transcriptome and characterizing the tumor’s immune microenvironment are crucial for the development of gene and immune therapies designed to target H3.3 G34R pHGG. Citation Format: Matthew J. Whalen, Maria B. Garcia-Fabiani, Felipe J. Núñez, Pedro R. Lowenstein, Maria G. Castro. Molecular characterization of a pediatric high-grade glioma (pHGG) mouse model harboring the H3.3 G34R mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 869.