Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by highly heterogeneous genomic alterations and altered signaling pathways, with limited studies on its proteome. Our study presents a comprehensive analysis of the proteome and phosphoproteome in B-CLL and CLL-like monoclonal B-cell lymph...

ver descrição completa

Detalhes bibliográficos
Autores: Díez, Paula, Juanes-Velasco, Pablo, García-Vaquero, Marina L., Droste, Conrad, Landeira-Viñuela, Alicia, Alcoceba, Miguel, Fidalgo-Gómez, Helena, Misiego-Herrero, Sara, Navarro-Bailón, Almudena, Baile, Mónica, Bastida, José María, Sánchez-Santos, José Manuel, Góngora, Rafael, Almeida, Julia, González-Díaz, Marcos, Orfao, Alberto, De Las Rivas, Javier, Fuentes, Manuel
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:dnet:digitalcsic_::3616416e584b10c2386608c20ac00e5a
Acesso em linha:http://hdl.handle.net/10261/427616
https://api.elsevier.com/content/abstract/scopus_id/105000856819
Access Level:acceso abierto
Palavra-chave:B-cell chronic lymphocytic leukemia
BCR signaling
Intracellular protein network
Phosphoproteome
Proteomics
Tyrosine kinase
id ES_54fbbb2d4f22fa4cd03f66932aeb168b
oai_identifier_str oai:dnet:digitalcsic_::3616416e584b10c2386608c20ac00e5a
network_acronym_str ES
network_name_str España
repository_id_str
spelling Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stagesDíez, PaulaJuanes-Velasco, PabloGarcía-Vaquero, Marina L.Droste, ConradLandeira-Viñuela, AliciaAlcoceba, MiguelFidalgo-Gómez, HelenaMisiego-Herrero, SaraNavarro-Bailón, AlmudenaBaile, MónicaBastida, José MaríaSánchez-Santos, José ManuelGóngora, RafaelAlmeida, JuliaGonzález-Díaz, MarcosOrfao, AlbertoDe Las Rivas, JavierFuentes, ManuelB-cell chronic lymphocytic leukemiaBCR signalingIntracellular protein networkPhosphoproteomeProteomicsTyrosine kinaseB-cell chronic lymphocytic leukemia (B-CLL) is characterized by highly heterogeneous genomic alterations and altered signaling pathways, with limited studies on its proteome. Our study presents a comprehensive analysis of the proteome and phosphoproteome in B-CLL and CLL-like monoclonal B-cell lymphocytosis (MBL) primary cells. Using high-resolution mass spectrometry, we identified 2970 proteins and 316 phosphoproteins across five tumor samples, including 55 newly identified phosphopeptides (ProteomeXchange-PXD005997). Our multifaceted approach also integrated protein microarrays and western blotting for further data validation in a new patient cohort of 14 patients. Despite sharing 73% of their proteomes, the phosphoproteomes varied significantly among samples, independent of cytogenetic alterations and immunoglobulin heavy variable cluster (IGHV) mutational status. We identified common functional hallmarks in B-CLL and MBL phosphoproteomes, notably tonic signaling (low-level, constitutive signaling) of the B-cell antigen-specific receptor (BCR) and nuclear factor NF-kappa-B (NF-kβ)/signal transducer and activator of transcription 3 (STAT3) pathways. Nine phosphoproteins involved in BCR signaling were further validated, showing a high correlation with early disease stages. Our study advances the field by providing a detailed perspective on the proteome and phosphoproteome of B-CLL cells, revealing signaling pathways crucial for disease development and progression. Integrating diverse proteomics techniques and identifying novel phosphopeptides offers new insights into CLL biology, potentially informing future therapeutic strategies and biomarker development for early diagnosis and personalized treatment.We gratefully acknowledge financial support from the Spanish Health Institute Carlos III (ISCIII) for the grants FIS PI21/01545, FIS PI17/01930, CB16/12/00400. We also acknowledge Fondos FEDER (EU), Junta Castilla-León (COVID19 grant COV20EDU/00187) and Fundación Solórzano (FS23/2015). The Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17 0019 0023, of the PE I + D + I 2017–2020, funded by ISCIII and FEDER. PD and CD are supported by a JCYL-EDU/346/2013 Ph.D. scholarship. AL-V is supported by VII Centenario-USAL PhD program. PJ-V is supported by JCYL PhD Program ‘Nos Impulsa-JCYL’ and scholarship JCYL-EDU/601/2020.Peer reviewedJohn Wiley & SonsInstituto de Salud Carlos IIIEuropean CommissionJunta de Castilla y LeónFundación Memoria de D. Samuel Solorzano BarrusoUniversidad de SalamancaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/427616https://api.elsevier.com/content/abstract/scopus_id/105000856819reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1002/1878-0261.70032https://doi.org/10.1002/1878-0261.70032Síinfo:eu-repo/semantics/openAccessoai:dnet:digitalcsic_::3616416e584b10c2386608c20ac00e5a2026-05-22T06:33:51Z
dc.title.none.fl_str_mv Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages
title Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages
spellingShingle Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages
Díez, Paula
B-cell chronic lymphocytic leukemia
BCR signaling
Intracellular protein network
Phosphoproteome
Proteomics
Tyrosine kinase
title_short Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages
title_full Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages
title_fullStr Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages
title_full_unstemmed Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages
title_sort Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages
dc.creator.none.fl_str_mv Díez, Paula
Juanes-Velasco, Pablo
García-Vaquero, Marina L.
Droste, Conrad
Landeira-Viñuela, Alicia
Alcoceba, Miguel
Fidalgo-Gómez, Helena
Misiego-Herrero, Sara
Navarro-Bailón, Almudena
Baile, Mónica
Bastida, José María
Sánchez-Santos, José Manuel
Góngora, Rafael
Almeida, Julia
González-Díaz, Marcos
Orfao, Alberto
De Las Rivas, Javier
Fuentes, Manuel
author Díez, Paula
author_facet Díez, Paula
Juanes-Velasco, Pablo
García-Vaquero, Marina L.
Droste, Conrad
Landeira-Viñuela, Alicia
Alcoceba, Miguel
Fidalgo-Gómez, Helena
Misiego-Herrero, Sara
Navarro-Bailón, Almudena
Baile, Mónica
Bastida, José María
Sánchez-Santos, José Manuel
Góngora, Rafael
Almeida, Julia
González-Díaz, Marcos
Orfao, Alberto
De Las Rivas, Javier
Fuentes, Manuel
author_role author
author2 Juanes-Velasco, Pablo
García-Vaquero, Marina L.
Droste, Conrad
Landeira-Viñuela, Alicia
Alcoceba, Miguel
Fidalgo-Gómez, Helena
Misiego-Herrero, Sara
Navarro-Bailón, Almudena
Baile, Mónica
Bastida, José María
Sánchez-Santos, José Manuel
Góngora, Rafael
Almeida, Julia
González-Díaz, Marcos
Orfao, Alberto
De Las Rivas, Javier
Fuentes, Manuel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Junta de Castilla y León
Fundación Memoria de D. Samuel Solorzano Barruso
Universidad de Salamanca
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv B-cell chronic lymphocytic leukemia
BCR signaling
Intracellular protein network
Phosphoproteome
Proteomics
Tyrosine kinase
topic B-cell chronic lymphocytic leukemia
BCR signaling
Intracellular protein network
Phosphoproteome
Proteomics
Tyrosine kinase
description B-cell chronic lymphocytic leukemia (B-CLL) is characterized by highly heterogeneous genomic alterations and altered signaling pathways, with limited studies on its proteome. Our study presents a comprehensive analysis of the proteome and phosphoproteome in B-CLL and CLL-like monoclonal B-cell lymphocytosis (MBL) primary cells. Using high-resolution mass spectrometry, we identified 2970 proteins and 316 phosphoproteins across five tumor samples, including 55 newly identified phosphopeptides (ProteomeXchange-PXD005997). Our multifaceted approach also integrated protein microarrays and western blotting for further data validation in a new patient cohort of 14 patients. Despite sharing 73% of their proteomes, the phosphoproteomes varied significantly among samples, independent of cytogenetic alterations and immunoglobulin heavy variable cluster (IGHV) mutational status. We identified common functional hallmarks in B-CLL and MBL phosphoproteomes, notably tonic signaling (low-level, constitutive signaling) of the B-cell antigen-specific receptor (BCR) and nuclear factor NF-kappa-B (NF-kβ)/signal transducer and activator of transcription 3 (STAT3) pathways. Nine phosphoproteins involved in BCR signaling were further validated, showing a high correlation with early disease stages. Our study advances the field by providing a detailed perspective on the proteome and phosphoproteome of B-CLL cells, revealing signaling pathways crucial for disease development and progression. Integrating diverse proteomics techniques and identifying novel phosphopeptides offers new insights into CLL biology, potentially informing future therapeutic strategies and biomarker development for early diagnosis and personalized treatment.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/427616
https://api.elsevier.com/content/abstract/scopus_id/105000856819
url http://hdl.handle.net/10261/427616
https://api.elsevier.com/content/abstract/scopus_id/105000856819
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1002/1878-0261.70032
https://doi.org/10.1002/1878-0261.70032
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv John Wiley & Sons
publisher.none.fl_str_mv John Wiley & Sons
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869408230608732160
score 15,81155

Registos relacionados