Biom-57. unraveling the dysregulation of mir-17/92 cluster in aggressive pediatric brain tumors: implications for novel therapeutic strategies

Abstract The miR-17/92 cluster, commonly referred to as “OncoMir-1,” is extensively studied in cancer due to its oncogenic role, but it has yet to be fully characterized in pediatric brain tumors. In this study, we conduct a comprehensive investigation involving miRNA profiling of 262 pediatric brain tumors, along with sample-matched data from the Pediatric Brain Tumor Atlas, including WGS, RNA-sequencing, proteomics, and phospho-proteomics data. Through miRNA-based unsupervised clustering, we identified four distinct miRNA signatures that transcend histological boundaries. An aggressive cluster (consisting of Medulloblastoma, ATRT, High-Grade Astrocytic Tumors, and some Ependymomas) exhibited the shortest survival and displayed an enriched network of co-expressed miR-17/92 cluster family members and paralogues, specifically miR-106b/25 and miR-106a/363 (p< 0.001). These tumors exhibited significant upregulation of the MIR17HG gene, which encodes the miR-17/92 cluster of miRNAs (p< 0.001). Further exploration of the upstream regulatory mechanisms of MIR17HG identified n-MYC and E2F1/2/3 significantly upregulated (p< 0.01). Additionally, utilizing sample-matched phospho-proteomics data, we found hyperphosphorylation of RB1, the upstream regulator of E2F, at three sites, providing additional evidence of RB1-E2F regulation upstream of MIR17HG. RB1 hyperphosphorylation and subsequent complete inactivation are mediated by the CDK2/Cyclin E complex, which is inhibited by the tumor suppressor p21. Interestingly, p21 (CDKN1A) gene expression was entirely depleted in the aggressive brain tumors group. In summary, our findings reveal the aberrant upregulation of the oncogenic miR-17/92 cluster in a group of aggressive brain tumors, potentially resulting from inactivating hyperphosphorylation of RB1 caused by p21 loss. This event frees E2F transcription factors and enables transcription of MIR17HG. Additionally, our study highlights E2F1/2/3 and CDK2 as potential therapeutic targets not only for aggressive brain tumors but also for other cancers overexpressing the miR-17/92 cluster. Future research will focus on molecular validation and targeting of the miR-17/92 regulatory pathway using available brain tumor cell line models.