B-cell-Specific Wwox Deletion Promotes Plasmablastic Tumor Development and Pro-Inflammatory Signatures in Myeloma Model Open Access

• Wwox deletion in Vk*MYC myeloma mice leads to aggressive plasmablastic tumors, reduced survival, and enhanced inflammatory signaling.

• WWOX loss drives genomic instability in plasmablastic tumors, promoting mutations in cancer and DNA damage response genes

Deletions and translocations affecting WWOX accompanied by loss of expression are frequently observed in B cell neoplasms and are linked to poor prognosis. Our previous research showed that Wwox deletion early in B cell development induces genomic instability, neoplastic transformation, and monoclonal gammopathies in mice. In this study, by crossing Cd19 Wwox knockout (KO) with Vk*MYC myeloma model mice, we generated a model with concurrent Wwox deletion and MYC activation, reproducing two common oncogenic alterations in B and plasma cell cancers. We observed that Vk*MYC:Wwox KO mice exhibited significantly reduced survival rates primarily due to the development of plasmablastic plasmacytomas and lymphomas. Transcriptome profiling from bone marrow derived Cd138+ plasma cells and plasmablastic tumors revealed enrichment of biofunctions related to tumorigenic phenotype and inflammation activation upon Wwox deletion in Vk*MYC mice. Wwox KO plasmablastic tumors displayed mutations affecting classical cancer genes, DNA damage response (DDR) genes, as well as overexpression of Aid/Apobec family members associated to hypermutation and DDR mutational signatures. These findings illustrate the significant pathobiological effects of B cell specific Wwox deletion and support a relevant role for WWOX loss of function in B cell neoplastic progression towards more aggressive phenotypes.