SOX11 modulates BCR signaling through the PAX5/CD19 axis for therapeutic targeting in BTK-resistant mantle cell lymphoma

Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma. Despite multiple approved Bruton tyrosine kinase inhibitors (BTKis), resistance to BTKi continues to pose a major clinical challenge. The transcription factor sex determining region Y-box 11 (SOX11) is expressed in most patients with MCL and is associated with poor outcomes. We have previously demonstrated SOX11-dependent B-cell receptor (BCR) signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling via the transcriptional activation of the PAX5/CD19 axis. The translational potential of these results is significant as single-cell RNA sequencing data show that 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 (B-cell lymphoma 2 [BCL2] inhibitor), and chimeric antigen receptor T-cell-resistant patient-derived xenograft models in vitro. SOX11i treatment reduced the tumor growth in vivo in an MCL xenograft model without any significant toxicity. SOX11 inhibition offers significant potential for patients with MCL, especially BTKi-resistant patients, by targeting upstream resistance mechanisms.