SOX11 Modulates BCR Signaling Through the PAX5/CD19 Axis for Therapeutic Targeting in BTK Resistant Mantle Cell Lymphoma Open Access

• SOX11 contributes to BTK resistance in MCL via the PAX5/CD19 axis directly increasing BCR and downstream signaling pathways.

• Targeting SOX11 overcomes BTK resistance by disrupting the BCR signaling pathway, leading to cell death in therapy-resistant MCL cells.

Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma (NHL). Despite multiple approved Bruton tyrosine kinase inhibitors (BTKi), resistance to BTKi continues to pose a major clinical challenge. The transcription factor SOX11 is expressed in most MCL patients and is associated with poor outcomes. We have previously demonstrated SOX11-dependent BCR signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling by transcriptional activation of the PAX5-CD19 axis. The translational potential of these results is significant as scRNA-seq data show SOX11 is overexpressed in Ibrutinib-resistant patients as compared to Ibrutinib-sensitive patients. Treatment with the SOX11 DNA-binding inhibitor (SOX11i) significantly reduces the expression of PAX5, CD19, and components of BCR signaling in both Ibrutinib-sensitive and Ibrutinib-resistant cell lines. Importantly, SOX11i was able to demonstrate cytotoxicity in cells derived from Ibrutinib-resistant, Venetoclax (BCL2i) and CAR-T resistant PDX models in vitro. SOX11i treatment reduced the tumor growth in vivo in a MCL xenograft model without any significant toxicity. SOX11 inhibition offers significant potential for MCL patients, especially BTKi resistant patients, by targeting upstream resistance mechanisms.