Abstract B011: Investigating how <i>Nf1</i> mutations differentially regulate pediatric high-grade and low-grade glioma penetrance

Abstract Studies have suggested that certain Nf1 mutations are correlated with higher or lower glioma incidence in humans. Additionally, the different Nf1 patient-derived mutations have different propensity to drive optic glioma formation, thus we aim to investigate the role of different germline Nf1 mutations in regulating glioma penetrance in the central nervous system. To do this, we generate several high-grade (HGG) and low-grade glioma (LGG) models using the different Nf1 mutant strains, and we will interrogate the microenvironmental and tumor changes in these mice. Currently, we have generated mice with germline mutation in the Tyr-2083 residue in the Nf1 gene (Y2083X). We electroporated sgRNAs targeting Nf1, Atrx, Cdkn2a, Trp53 (HGG group 1), Nf1, Atrx, Cdkn2a (HGG group 2), and Nf1 (LGG group 1). For LGG group 2, we combined sgRNA targeting Nf1 with either a transposable Fgf1-expressing plasmid to simulate Fgf1 amplification in NF1-LGGs or a plasmid expressing Fgfr1 activating mutation (N546K). We will assess survival of these mice comparing Nf1-wildtype and Nf1-heterozygous mutant mice. Additionally, we will conduct pathological analysis of tumor and immune populations in these mice and perform single cell transcriptomics of tumor and microenvironment cell populations. We also plan to determine the role of neuronal activity in the pathogenesis of NF1-gliomas by investigating the effect of pharmacological inhibition of activity-dependent factors in these mice. We hypothesized that Nf1 germline mutations will accelerate NF1- HGG formation when combined with somatic mutations such as Atrx, Cdkn2a, Trp53, and Nf1 loss of heterozygosity, whereas the germline Nf1 mutations will differentially contribute to the pathogenesis of NF1-LGG. Citation Format: Griselda M Yvone, Paul W Linesch, Naomi Kobritz, Eddie Lu, Yuan Pan, David H Gutmann, Joshua J Breunig. Investigating how Nf1 mutations differentially regulate pediatric high-grade and low-grade glioma penetrance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr B011.