Wwox Deletion in mouse B Cells leads to genomic instability, neoplastic transformation and monoclonal gammopathies

MCBRIDE KM; KIL H; MU Y; PLUMMER JB; LEE J; ZELAZOWSKI MJ; SEBASTIAN M; ABBA MC; ALDAZ CM

Frontiers in Oncology

Frontiers Media SA

Año: 2019

2234-943X

WWOX (WW domain containing oxidoreductase) expression loss is common in various cancers and characteristic of poor prognosis.Deletions, translocations and loss of expression affecting the WWOX gene are a common feature of various B cell neoplasms such ascertain B cell lymphomas and multiple myeloma. However, the role of this common abnormality in B cell tumor initiation and/orprogression has not been defined. In this study, we conditionally deleted Wwox early in B cell development by means of breedingCd19-Cre transgenic mice crossed to Wwox floxed mice (Cd19 Wwox KO). We observed a significant reduced survival in Cd19Wwox KO mice and the development of B cell neoplasms including B cell lymphomas, plasma cell neoplasias characterized byincreased numbers of CD138+ populations as well as monoclonal gammopathies detected by serum protein electrophoresis. Toinvestigate whether Wwox loss could play a role in genomic instability, we analyzed DNA repair functions during immunoglobulinclass switch joining between DNA segments in antibody genes. While class switch recombination (CSR) was only slightly impaired,Wwox deficiency resulted in a dramatic shift of double strand break repair from normal classical-NHEJ, toward themicrohomology-mediated alternative-NHEJ pathway, a pathway associated with chromosome translocations and genomeinstability. Consistent with this, Wwox deficiency resulted in a marked increase of spontaneous translocations during CSR. Thiswork defines for the first time a role for Wwox for maintaining B cell genome stability during a process that can promoteneoplastic transformation and monoclonal gammopathies.