Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies

WWOX( WW domaincontaining oxidoreductase) expression loss is common in various cancers and characteristic of poor prognosis. Deletions, translocations and loss of expression affecting the WWOXgene are a common feature of various B cell neoplasms such as certain B cell lymphomasand multiple myeloma. However, the role of this common abnormality in B cell tumor initiationand/or progression has not been defined. In this study, we conditionally deleted Wwoxearly in B cell development by means of breeding Cd19-Cre transgenic mice crossed to Wwox floxedmice ( Cd19 WwoxKO). We observed a significant reduced survival in Cd19 WwoxKO mice and the development of B cell neoplasms including B cell lymphomas, plasma cell neoplasias characterized by increased numbers of CD138+ populations as well as monoclonal gammopathiesdetected by serum protein electrophoresis. To investigate whether Wwoxloss could play a role in genomic instability, we analyzed DNA repair functions during immunoglobulin class switchjoining between DNA segments in antibody genes. While class switch recombination (CSR) was only slightly impaired, Wwoxdeficiency resulted in a dramatic shift of double strand break repair from normal classical-NHEJ, toward the microhomology-mediated alternative-NHEJ pathway, a pathway associated with chromosome translocationsand genome instability. Consistent with this, Wwoxdeficiency resulted in a marked increase of spontaneous translocations during CSR. This work defines for the first time a role for Wwoxfor maintaining B cell genome stability during a process that can promote neoplastic transformation and monoclonal gammopathies.