P01.26.B M6A-MEDIATED UPREGULATION OF SOX11 DRIVES CHROMATIN REMODELING AND STEMNESS, CONTRIBUTING TO THERAPEUTIC RESISTANCE IN H3 K27M-MUTANT SPINAL CORD GLIOMAS

Abstract BACKGROUND Spinal cord gliomas are rare intramedullary tumors (0.25-0.4/100,000 annually) with distinct molecular features compared to intracranial gliomas. H3 K27M-mutant spinal gliomas show strong stem-like traits and intrinsic resistance to therapy. Our preliminary data identified m6A modification as a positive regulator of SOX11, a transcription factor highly expressed in these tumors. SOX11 knockdown reduces chromatin accessibility and suppresses stemness-related genes. MATERIAL AND METHODS SOX11 expression was analyzed via public datasets and validated by IHC, western blot, and qPCR in glioma samples. Its function was studied through knockdown/overexpression in vitro and orthotopic models. m6A regulation of SOX11 was assessed by RIP, m6A-RIP, and RNA stability assays. SOX11-SWI/SNF interactions were analyzed by co-IP, and CUT&RUN plus ATAC-seq were used to assess chromatin accessibility and transcriptional changes. RESULTS m6A modification was found to upregulate SOX11 expression, enhancing chromatin accessibility at stemness-associated loci. SOX11 physically interacted with SWI/SNF complex components, promoting the transcription of genes linked to stemness and therapeutic resistance. Functional assays demonstrated that SOX11 knockdown impaired tumor cell self-renewal and markedly increased sensitivity to radiotherapy and temozolomide in both in vitro and orthotopic xenograft models. CONCLUSION Our findings identify a novel m6A-SOX11-SWI/SNF axis that promotes chromatin remodeling and maintains stemness in H3 K27M-mutant spinal gliomas, contributing to their intrinsic therapeutic resistance. Targeting this epigenetic pathway may offer a potential strategy to overcome treatment resistance in this aggressive tumor subtype.