Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies

Autores
McBride, Kevin M.; Kil, Hyunsuk; Mu, Yunxiang; Plummer, Joshua B.; Lee, Jaeho; Zelazowski, Maciej J.; Sebastian, Manu; Abba, Martín Carlos; Aldaz, Claudio Marcelo
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: McBride, Kevin M.. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Kil, Hyunsuk. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Mu, Yunxiang. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Plummer, Joshua B.. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Lee, Jaeho. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Zelazowski, Maciej J.. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Sebastian, Manu. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Aldaz, Claudio Marcelo. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Materia
B CELLS
GENOMIC INSTABILITY
MONOCLONAL GAMMOPATHIES
MULTIPLE MYELOMA
PLASMACYTOMAS
WWOX
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/128735

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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathiesMcBride, Kevin M.Kil, HyunsukMu, YunxiangPlummer, Joshua B.Lee, JaehoZelazowski, Maciej J.Sebastian, ManuAbba, Martín CarlosAldaz, Claudio MarceloB CELLSGENOMIC INSTABILITYMONOCLONAL GAMMOPATHIESMULTIPLE MYELOMAPLASMACYTOMASWWOXhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1WWOX (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.Fil: McBride, Kevin M.. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Kil, Hyunsuk. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Mu, Yunxiang. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Plummer, Joshua B.. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Lee, Jaeho. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Zelazowski, Maciej J.. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Sebastian, Manu. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Aldaz, Claudio Marcelo. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFrontiers Media S.A.2019-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/128735McBride, Kevin M.; Kil, Hyunsuk; Mu, Yunxiang; Plummer, Joshua B.; Lee, Jaeho; et al.; Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies; Frontiers Media S.A.; Frontiers in Oncology; 9; JUN; 6-2019; 1-112234-943XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fonc.2019.00517/abstractinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fonc.2019.00517info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:31:54Zoai:ri.conicet.gov.ar:11336/128735instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:31:55.246CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies
title Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies
spellingShingle Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies
McBride, Kevin M.
B CELLS
GENOMIC INSTABILITY
MONOCLONAL GAMMOPATHIES
MULTIPLE MYELOMA
PLASMACYTOMAS
WWOX
title_short Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies
title_full Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies
title_fullStr Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies
title_full_unstemmed Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies
title_sort Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies
dc.creator.none.fl_str_mv McBride, Kevin M.
Kil, Hyunsuk
Mu, Yunxiang
Plummer, Joshua B.
Lee, Jaeho
Zelazowski, Maciej J.
Sebastian, Manu
Abba, Martín Carlos
Aldaz, Claudio Marcelo
author McBride, Kevin M.
author_facet McBride, Kevin M.
Kil, Hyunsuk
Mu, Yunxiang
Plummer, Joshua B.
Lee, Jaeho
Zelazowski, Maciej J.
Sebastian, Manu
Abba, Martín Carlos
Aldaz, Claudio Marcelo
author_role author
author2 Kil, Hyunsuk
Mu, Yunxiang
Plummer, Joshua B.
Lee, Jaeho
Zelazowski, Maciej J.
Sebastian, Manu
Abba, Martín Carlos
Aldaz, Claudio Marcelo
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv B CELLS
GENOMIC INSTABILITY
MONOCLONAL GAMMOPATHIES
MULTIPLE MYELOMA
PLASMACYTOMAS
WWOX
topic B CELLS
GENOMIC INSTABILITY
MONOCLONAL GAMMOPATHIES
MULTIPLE MYELOMA
PLASMACYTOMAS
WWOX
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: McBride, Kevin M.. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Kil, Hyunsuk. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Mu, Yunxiang. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Plummer, Joshua B.. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Lee, Jaeho. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Zelazowski, Maciej J.. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Sebastian, Manu. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Aldaz, Claudio Marcelo. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
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.
publishDate 2019
dc.date.none.fl_str_mv 2019-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/128735
McBride, Kevin M.; Kil, Hyunsuk; Mu, Yunxiang; Plummer, Joshua B.; Lee, Jaeho; et al.; Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies; Frontiers Media S.A.; Frontiers in Oncology; 9; JUN; 6-2019; 1-11
2234-943X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/128735
identifier_str_mv McBride, Kevin M.; Kil, Hyunsuk; Mu, Yunxiang; Plummer, Joshua B.; Lee, Jaeho; et al.; Wwox seletion in mouse B cells leads to genomic instability, neoplastic transformation, and monoclonal gammopathies; Frontiers Media S.A.; Frontiers in Oncology; 9; JUN; 6-2019; 1-11
2234-943X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fonc.2019.00517/abstract
info:eu-repo/semantics/altIdentifier/doi/10.3389/fonc.2019.00517
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media S.A.
publisher.none.fl_str_mv Frontiers Media S.A.
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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