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

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 as certain B cell lymphomas and multiple myelo...

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Autores principales: McBride, Kevin M., Kil, Hyunsuk, Mu, Yunxiang, Plummer, Joshua B., Lee, Jaeho, Zelazowski, Maciej J., Sebastian, Manu M., Abba, Martín Carlos, Aldaz, C. Marcelo
Formato: Articulo
Lenguaje:Inglés
Publicado: 2019
Materias:
Medicina
Wwox
B cells
monoclonal gammopathies
plasmacytomas
multiple myeloma
genomic instability
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/128773
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-128773
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Medicina
Wwox
B cells
monoclonal gammopathies
plasmacytomas
multiple myeloma
genomic instability
spellingShingle Medicina
Wwox
B cells
monoclonal gammopathies
plasmacytomas
multiple myeloma
genomic instability
McBride, Kevin M.
Kil, Hyunsuk
Mu, Yunxiang
Plummer, Joshua B.
Lee, Jaeho
Zelazowski, Maciej J.
Sebastian, Manu M.
Abba, Martín Carlos
Aldaz, C. Marcelo
Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies
topic_facet Medicina
Wwox
B cells
monoclonal gammopathies
plasmacytomas
multiple myeloma
genomic instability
description 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 as certain B cell lymphomas and multiple myeloma. However, the role of this common abnormality in B cell tumor initiation and/or progression has not been defined. In this study, we conditionally deleted Wwox early in B cell development by means of breeding Cd19-Cre transgenic mice crossed to Wwox floxed mice (Cd19 Wwox KO). We observed a significant reduced survival in Cd19 Wwox KO 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 gammopathies detected by serum protein electrophoresis. To investigate whether Wwox loss could play a role in genomic instability, we analyzed DNA repair functions during immunoglobulin class 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 (DSB) repair from normal classical-NHEJ toward the microhomology-mediated alternative-NHEJ pathway, a pathway associated with chromosome translocations and genome instability. Consistent with this, Wwox deficiency resulted in a marked increase of spontaneous translocations during CSR. This work defines for the first time a role for Wwox for maintaining B cell genome stability during a process that can promote neoplastic transformation and monoclonal gammopathies.
format Articulo
Articulo
author McBride, Kevin M.
Kil, Hyunsuk
Mu, Yunxiang
Plummer, Joshua B.
Lee, Jaeho
Zelazowski, Maciej J.
Sebastian, Manu M.
Abba, Martín Carlos
Aldaz, C. Marcelo
author_facet McBride, Kevin M.
Kil, Hyunsuk
Mu, Yunxiang
Plummer, Joshua B.
Lee, Jaeho
Zelazowski, Maciej J.
Sebastian, Manu M.
Abba, Martín Carlos
Aldaz, C. Marcelo
author_sort McBride, Kevin M.
title Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies
title_short Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies
title_full Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies
title_fullStr Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies
title_full_unstemmed Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies
title_sort wwox deletion in mouse b cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies
publishDate 2019
url http://sedici.unlp.edu.ar/handle/10915/128773
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