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.
Dutta et al. (Fri,) studied this question.