B-cell-specific Wwox deletion promotes plasmablastic tumor development and proinflammatory signatures in myeloma...

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 2 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 toward more aggressive phenotypes.