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

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. Overall design: RNA sequencing analysis of Vk*MYC:Wwox WT-BM (n=3), Vk*MYC:Wwox KO-BM (n=3), and Vk*MYC:Wwox KO-PBT (n=4) samples to evaluate comparative gene expression changes between Vk*MYC:Wwox WT-BM vs KO-BM and Vk*MYC:Wwox KO-BM vs KO-PBT groups.