HGG-07. OVEREXPRESSION OF A PLAG-FAMILY TRANSCRIPTION FACTOR DURING MURINE BRAIN DEVELOPMENT CAUSES BRAIN TUMOR FORMATION

Abstract

Abstract Pediatric-type gliomas are the most common type of central nervous system tumors in children. They are highly diverse regarding their molecular entities and clinical associations, and they differ from their adult counterparts. A subset of pediatric-type high grade gliomas, including H3K27M mutated diffuse midline glioma, overexpresses the developmentally regulated transcription factor gene PLAG1. Two novel tumor types displaying amplifications or fusions with the related PLAGL1 and PLAGL2 genes have also recently been described (PMIDs 36437415, 34355256). How PLAG-family dysregulation drives tumor formation is currently unknown, however. We generated a novel mouse model that overexpresses hPLAG1 during brain development using a Cre-LoxP approach. Mice that overexpress hPLAG1 together with loss of trp53 in the Nestin-Cre lineage develop brain tumors by 3 months of age with 100 % penetrance. Intriguingly, tumors develop in different brain regions, with hotspots in the thalamus or inferior hypothalamus, the latter likely emerging from the brainstem. All mouse brains contain regions in the brainstem, thalamus and the prefrontal cortex with diffuse patterns of PLAG1+; KI67+ proliferating single cells. Using bulk-RNA sequencing, we identified several genes involved in embryonic brain development, which are still active in the tumors of adult mice. We hypothesize that continued overexpression of PLAG1 locks cells in an aberrant developmental state, making them susceptible for further oncogenic hits and ultimately leading to pediatric glioma formation. We are currently using single-nucleus RNA-seq to determine the developmental trajectories of single tumor cells to identify putative cells-of-origin and primary developmental pathways. Our work will elucidate the consequences of PLAG1 overexpression in pediatric brain tumors and its contribution to tumorigenesis. In the future, we hope to identify genetic dependencies of PLAG1 to generate novel treatment options.