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

Deletions and translocations affecting <i>WWOX</i> accompanied by loss of expression are frequently observed in B-cell neoplasms and are linked to poor prognosis. Our previous research showed that <i>Wwox</i> deletion early in B-cell development induces genomic instability, neoplastic transformation, and monoclonal gammopathies in mice. In this study, by crossing <i>Cd19 Wwox</i> knockout (KO) with <i>Vk^∗MYC</i> myeloma model mice, we generated a model with concurrent <i>Wwox</i> deletion and <i>MYC</i> activation, reproducing 2 common oncogenic alterations in B- and plasma-cell cancers. We observed that <i>Vk^∗MYC:Wwox KO</i> 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 <i>Wwox</i> deletion in <i>Vk^∗MYC</i> mice. <i>Wwox KO</i> 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 <i>Wwox</i> deletion and support a relevant role for WWOX loss of function in B-cell neoplastic progression toward more aggressive phenotypes.