The SOX11:SMARCA4 complex is a driver of oncogenic transcriptional programs in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is considered one of the most aggressive B-cell lymphoid neoplasms. The transcription factor SOX11 is aberrantly expressed in conventional aggressive MCL, while it is not or weakly expressed in the leukemic non-nodal MCL subtype with a predominantly indolent clinical evolution. SOX11 is a key driver of MCL through the regulation of several oncogenic mechanisms, suggesting that it may be interacting with different protein complexes to exert its multiple actions. Using proteomic strategies, we characterized the SOX11-interactome and validated its physical interaction with SMARCA4, the catalytic subunit of the SWI/SNF chromatin-remodeling complex. SMARCA4 expression is directly regulated by SOX11, and its upregulation significantly associates with worse outcomes of patients. Integration of global DNA-binding and transcriptomic profiles revealed that SOX11 and SMARCA4 share binding sites enriched in open chromatin and active promoters and regulate common key oncogenic pathways crucial for MCL progression and aggressiveness. The SMARCA4-specific PROTAC-degrader AU-15330 significantly reduced SOX11 binding to specific regulatory regions and diminished the activation of BCR-, NIK-, and BCL2-signaling pathways. Moreover, SMARCA4 degradation significantly reduced proliferation and induced apoptosis of SOX11-positive MCL cells, highlighting AU-15330 as a promising therapeutic approach for patients who may relapse from current target therapies in MCL.