Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma

SOX11 overexpression has been associated with aggressive behavior of mantle cell lymphomas (MCL). SOX11 is overexpressed in embryonic and cancer stem cells (CSC) of some tumors. Although CSC have been isolated from primary MCL, their relationship to SOX11 expression and contribution to MCL pathogenesis and clinical evolution remain unknown. Here, we observed enrichment in leukemic and hematopoietic stem cells gene signatures in SOX11+ compared to SOX11- MCL primary cases. Musashi-2 (MSI2) emerged as one of the most significant upregulated stem cell-related genes in SOX11+ MCLs. SOX11 is directly bound to the MSI2 promoter upregulating its expression in vitro. MSI2 intronic enhancers were strongly activated in SOX11+ MCL cell lines and primary cases. MSI2 upregulation was significantly associated with poor overall survival independently of other high-risk features of MCL. MSI2 knockdown decreased the expression of genes related to apoptosis and stem cell features and significantly reduced clonogenic growth, tumor cell survival and chemoresistance in MCL cells. MSI2-knockdown cells had reduced tumorigenic engraftment into mice bone marrow and spleen compared to control cells in xenotransplanted mouse models. Our results suggest that MSI2 might play a key role in sustaining stemness and tumor cell survival, representing a possible novel target for therapeutic interventions in MCL.

Automated summary

SOX11 overexpression is associated with aggressive behavior in mantle cell lymphomas (MCL). This study finds that SOX11+ MCL cases show enrichment in gene signatures related to leukemic and hematopoietic stem cells, and Musashi-2 (MSI2) is identified as one of the upregulated stem cell-related genes. SOX11 directly binds to the MSI2 promoter and upregulates MSI2 expression. MSI2 upregulation is independently associated with poor overall survival in MCL, and its knockdown leads to decreased expression of genes related to apoptosis and stem cell features, reduced clonogenic growth, tumor cell survival, and chemoresistance in MCL cells.