SOX11-SMARCA4 Complex Drives Oncogenic Gene Regulation in Mantle Cell Lymphoma

SOX11 pioneer transcription factor is aberrantly expressed, it has an oncogenic role and its overexpression associates with worse prognosis in patients with mantle cell lymphomas (MCL). Using a proximity labeling (BioID2)/Mass Spectrometry-based proteomic strategyies, we identified SMARCA4, the central catalytic subunit of the SWI/SNF chromatin-remodeling complex, as one of the most significant SOX11-specific interacting proteins. SMARCA4 expression is directly regulated by SOX11, and its upregulation is associated with worse overall survival in patients with MCL, independently of other high-risk factors. Integration of global DNA-binding and transcriptomic profiles revealed that SOX11 and SMARCA4 share 60% specific peaks, predominantly in promoter regions. Disruption of SOX11:SMARCA4 interaction via SOX11 knockout or SMARCA4 PROTAC-degradation significantly reduced co-occupancy and co-targeted gene expression, including key BCR signaling pathway components. Our results suggest that SOX11:SMARCA4 complex binds to common regulatory sequences enabling the accession to chromatin and transcriptomic regulation of key oncogenic pathways for the development of MCL pathogenesis.