Hgg-24. a novel oncogenic role for menin in glioma

Abstract High-grade gliomas (HGGs) represent the most common subtype of primary malignant tumors from brain or spinal cord. With about 18 months overall survival time, HGGs is the leading cause of death from primary brain tumor. Survival outcomes have not improved significantly over the past two decades despite major research and therapeutic discovery efforts. Previous work from our lab suggested a role for menin in initiation and maintenance of pediatric high-grade glioma. Here we describe a critical oncogenic role of menin (encoded by the MEN1 gene) in maintaining HGGs proliferation. Using a panel of early passage HGG lines harboring diverse genomic alterations, we demonstrate that silencing of MEN1 blocks proliferation (60%-80%) of a subset (8/12) of HGGs, independent of their genomic alteration profile. An oncogenic role of menin has been described in MLL-rearrangement leukemia, where menin complexes with MLL to affect H3K4 trimethylation and activate leukemogenic genes. However, we found that the menin-MLL interaction is not associated with glioma. Instead, our mechanistic studies suggest that menin plays a critical role in maintaining H3K27 acetylation marks across the genome. Using immunoprecipitation and mass spectrometry, we identified HMGN1 (high mobility group nucleosome-binding domain 1 protein) as a putative novel menin partner. HMGN1 is a chromatin remodeling protein associated with chromatin accessibility and H3K27 acetylation. Transcriptional studies of patient-derived HGGs revealed that knockout of MEN1 and silencing of HMGN1 both resulted in broad repression of genes associated with proliferative tumor progenitor clusters. Ongoing work is aimed at therapeutic targeting by novel menin inhibitors. Our work demonstrates the role of epigenetic remodeling in controlling glioma proliferation and identifying novel therapeutic targets.