Sox11 Modulates Redox Homeostasis and Chemoresistance via Tcl1a and Prdx2 Upregulation in Aggressive Mcl

Abstract Mantle cell lymphoma (MCL) is an incurable B-cell neoplasm characterized by its aggressive behavior, short responses to conventional therapies and SOX11 overexpression. Oxidative stress is known to induce tumorigenesis and tumor progression, whereas high levels of antioxidant genes have been associated with chemoresistance in different cancers. However, the role of oxidative stress in MCL pathogenesis and the involvement of SOX11 regulating redox homeostasis in MCL cells are largely unknown. Here, we observed that aggressive SOX11 + MCL presented higher reactive oxygen species (ROS) levels and increased expression of oxidative stress-related genes compared to SOX11- MCL primary cases. Upregulation of the antioxidant gene PRDX2 and the proto-oncogene TCL1A significantly correlated with SOX11 overexpression and associated with worse patients’ overall survival. SOX11 knockout (SOX11KO) significantly reduced TCL1A. Moreover, SOX11KO and TCL1A knockdown (TCL1AKD) reduced PRDX2 expression in MCL cell lines. SOX11KO, TCL1AKD and PRDX2KD increased ROS levels and tumor cell death upon drug treatment in vitro. Interestingly, TCL1AKD reduced tumor growth in vivo, suggesting its involvement in MCL tumorigenesis. Overall, our results suggest an aberrant redox homeostasis associated with chemoresistance in aggressive MCL through TCL1A and PRDX2 upregulation, highlighting them as promising targets for new therapeutic strategies to overcome chemoresistance in aggressive MCLs.