Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis

[EN]Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T-cell lymphoma (PTCL), non-small cell lung cancer, and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 c...

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Autores: Robles Valero, Javier, Fernández‐Nevado, Lucía, Lorenzo Martín, L. Francisco, Fernández‐Pisonero, Isabel, Rodríguez‐Fdez, Sonia, Astorga‐Simón, Elsa N
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2021
País:España
Recursos:Universidad de Salamanca (USAL)
Repositório:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/168546
Acesso em linha:http://hdl.handle.net/10366/168546
Access Level:Acceso aberto
Palavra-chave:Angioimmunoblastic T-cell lymphoma
Follicular helper T cells
Oncogene
Peripheral T-cell lymphoma
Tumor suppressor
GTPases
Lymphoma
Animals
Humans
CD4-Positive T-Lymphocytes
rac1 GTP-Binding Protein
Cell Proliferation
COS Cells
3201.01 Oncología
linfoma
linfocitos T CD4-positivos
animales
humanos
proteína de unión al GTP rac1
proliferación celular
células COS
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oai_identifier_str oai:gredos.usal.es:10366/168546
network_acronym_str ES
network_name_str España
repository_id_str
spelling Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesisRobles Valero, JavierFernández‐Nevado, LucíaLorenzo Martín, L. FranciscoFernández‐Pisonero, IsabelRodríguez‐Fdez, SoniaAstorga‐Simón, Elsa NAngioimmunoblastic T-cell lymphomaFollicular helper T cellsOncogenePeripheral T-cell lymphomaTumor suppressorGTPasesLymphomaAnimalsHumansCD4-Positive T-Lymphocytesrac1 GTP-Binding ProteinCell ProliferationCOS Cells3201.01 Oncologíalinfomalinfocitos T CD4-positivosanimaleshumanosproteína de unión al GTP rac1proliferación celularcélulas COS[EN]Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T-cell lymphoma (PTCL), non-small cell lung cancer, and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer-associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional impact on the three main VAV1 signaling branches, GEF-dependent activation of RAC1, GEF-independent adaptor-like, and tumor suppressor functions. These mutations target new and previously established regulatory layers of the protein, leading to quantitative and qualitative changes in VAV1 signaling output. We also demonstrate that the most frequent VAV1 mutant subtype drives PTCL formation in mice. This process requires the concurrent engagement of two downstream signaling branches that promote the chronic activation and transformation of follicular helper T cells. Collectively, these data reveal the genetic constraints associated with the lymphomagenic potential of VAV1 mutant subsets, similarities with other PTCL driver genes, and potential therapeutic vulnerabilities.Springer Nature Link202620262021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10366/168546reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)InglésHR20-00164RTI2018-096481-B-100PI20/01724Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1685462026-06-07T06:28:51Z
dc.title.none.fl_str_mv Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis
title Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis
spellingShingle Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis
Robles Valero, Javier
Angioimmunoblastic T-cell lymphoma
Follicular helper T cells
Oncogene
Peripheral T-cell lymphoma
Tumor suppressor
GTPases
Lymphoma
Animals
Humans
CD4-Positive T-Lymphocytes
rac1 GTP-Binding Protein
Cell Proliferation
COS Cells
3201.01 Oncología
linfoma
linfocitos T CD4-positivos
animales
humanos
proteína de unión al GTP rac1
proliferación celular
células COS
title_short Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis
title_full Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis
title_fullStr Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis
title_full_unstemmed Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis
title_sort Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis
dc.creator.none.fl_str_mv Robles Valero, Javier
Fernández‐Nevado, Lucía
Lorenzo Martín, L. Francisco
Fernández‐Pisonero, Isabel
Rodríguez‐Fdez, Sonia
Astorga‐Simón, Elsa N
author Robles Valero, Javier
author_facet Robles Valero, Javier
Fernández‐Nevado, Lucía
Lorenzo Martín, L. Francisco
Fernández‐Pisonero, Isabel
Rodríguez‐Fdez, Sonia
Astorga‐Simón, Elsa N
author_role author
author2 Fernández‐Nevado, Lucía
Lorenzo Martín, L. Francisco
Fernández‐Pisonero, Isabel
Rodríguez‐Fdez, Sonia
Astorga‐Simón, Elsa N
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Angioimmunoblastic T-cell lymphoma
Follicular helper T cells
Oncogene
Peripheral T-cell lymphoma
Tumor suppressor
GTPases
Lymphoma
Animals
Humans
CD4-Positive T-Lymphocytes
rac1 GTP-Binding Protein
Cell Proliferation
COS Cells
3201.01 Oncología
linfoma
linfocitos T CD4-positivos
animales
humanos
proteína de unión al GTP rac1
proliferación celular
células COS
topic Angioimmunoblastic T-cell lymphoma
Follicular helper T cells
Oncogene
Peripheral T-cell lymphoma
Tumor suppressor
GTPases
Lymphoma
Animals
Humans
CD4-Positive T-Lymphocytes
rac1 GTP-Binding Protein
Cell Proliferation
COS Cells
3201.01 Oncología
linfoma
linfocitos T CD4-positivos
animales
humanos
proteína de unión al GTP rac1
proliferación celular
células COS
description [EN]Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T-cell lymphoma (PTCL), non-small cell lung cancer, and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer-associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional impact on the three main VAV1 signaling branches, GEF-dependent activation of RAC1, GEF-independent adaptor-like, and tumor suppressor functions. These mutations target new and previously established regulatory layers of the protein, leading to quantitative and qualitative changes in VAV1 signaling output. We also demonstrate that the most frequent VAV1 mutant subtype drives PTCL formation in mice. This process requires the concurrent engagement of two downstream signaling branches that promote the chronic activation and transformation of follicular helper T cells. Collectively, these data reveal the genetic constraints associated with the lymphomagenic potential of VAV1 mutant subsets, similarities with other PTCL driver genes, and potential therapeutic vulnerabilities.
publishDate 2021
dc.date.none.fl_str_mv 2021
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10366/168546
url http://hdl.handle.net/10366/168546
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv HR20-00164
RTI2018-096481-B-100
PI20/01724
dc.rights.none.fl_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature Link
publisher.none.fl_str_mv Springer Nature Link
dc.source.none.fl_str_mv reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname:Universidad de Salamanca (USAL)
instname_str Universidad de Salamanca (USAL)
reponame_str GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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