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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/128735
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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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1846082805599043584 |
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13.22299 |