Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia

Mutations in genes of the RAS-BRAF-MAPK-ERK pathwayhave not been fully explored in patients with chronic lym-phocytic leukemia. We, therefore, analyzed the clinical andbiological characteristics of chronic lymphocytic leukemia patientswith mutations in this pathway and investigated thein vitrorespon...

Descripción completa

Detalles Bibliográficos
Autores: Giménez Carabaza, Neus, Martínez Trillos, Alejandra, Montraveta, Arnau, López-Guerra, Mónica, Rosich, Laia, Nadeu Prat, Ferran, Valero, Juan G., Aymerich Gregorio, Marta, Magnano, Laura, Rozman, María, Matutes, Estella, Delgado, Julio (Delgado González), Baumann, Tycho, Giné Soca, Eva, González, Marcos, Alcoceba, Miguel, Terol, Maria José, Navarro, Blanca, Colado, Enrique, Payer, Ángel R., Puente, Xose S., López-Otin, Carlos, López Guillermo, Armando, Campo Güerri, Elias, Colomer Pujol, Dolors, Villamor i Casas, Neus
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/148047
Acceso en línea:https://hdl.handle.net/2445/148047
Access Level:acceso abierto
Palabra clave:Leucèmia limfocítica crònica
Mutació (Biologia)
Chronic lymphocytic leukemia
Mutation (Biology)
id ES_eab0442e5d2eea7b8b918d2ced00fd12
oai_identifier_str oai:recercat.cat:2445/148047
network_acronym_str ES
network_name_str España
repository_id_str
spelling Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemiaGiménez Carabaza, NeusMartínez Trillos, AlejandraMontraveta, ArnauLópez-Guerra, MónicaRosich, LaiaNadeu Prat, FerranValero, Juan G.Aymerich Gregorio, MartaMagnano, LauraRozman, MaríaMatutes, EstellaDelgado, Julio (Delgado González)Baumann, TychoGiné Soca, EvaGonzález, MarcosAlcoceba, MiguelTerol, Maria JoséNavarro, BlancaColado, EnriquePayer, Ángel R.Puente, Xose S.López-Otin, CarlosLópez Guillermo, ArmandoCampo Güerri, EliasColomer Pujol, DolorsVillamor i Casas, NeusLeucèmia limfocítica crònicaMutació (Biologia)Chronic lymphocytic leukemiaMutation (Biology)Mutations in genes of the RAS-BRAF-MAPK-ERK pathwayhave not been fully explored in patients with chronic lym-phocytic leukemia. We, therefore, analyzed the clinical andbiological characteristics of chronic lymphocytic leukemia patientswith mutations in this pathway and investigated thein vitroresponseof primary cells to BRAF and ERK inhibitors. Putative damaging muta-tions were found in 25 of 452 patients (5.5%). Among these, BRAFwas mutated in nine patients (2.0%), genes upstream of BRAF(KITLG,KIT, PTPN11, GNB1, KRASand NRAS) were mutated in 12 patients(2.6%), and genes downstream of BRAF(MAPK2K1, MAPK2K2, andMAPK1) were mutated in five patients (1.1%). The most frequentmutations were missense, subclonal and mutually exclusive. Patientswith these mutations more frequently had increased lactate dehydro-genase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12and unmutated immunoglobulin heavy-chain variable region genesand had a worse 5-year time to first treatment (hazard ratio 1.8,P=0.025). Gene expression analysis showed upregulation of genes ofthe MAPK pathway in the group carrying RAS-BRAF-MAPK-ERKpathway mutations. The BRAF inhibitors vemurafenib and dabrafenibwere not able to inhibit phosphorylation of ERK, the downstreameffector of the pathway, in primary cells. In contrast, ulixertinib, apan-ERK inhibitor, decreased phospho-ERK levels. In conclusion,although larger series of patients are needed to corroborate these find-ings, our results suggest that the RAS-BRAF-MAPK-ERK pathway isone of the core cellular processes affected by novel mutations inchronic lymphocytic leukemia, is associated with adverse clinical fea-tures and could be pharmacologically inhibited.Ferrata Storti Foundation2020202020192020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion11 p.application/pdfhttps://hdl.handle.net/2445/148047Articles publicats en revistes (Fonaments Clínics)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3324/haematol.2018.196931Haematologica, 2019, vol. 104, num. 3, p. 576-586https://doi.org/10.3324/haematol.2018.196931info:eu-repo/grantAgreement/EC/FP7/306240(c) Ferrata Storti Foundation, 2018info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1480472026-05-29T05:05:01Z
dc.title.none.fl_str_mv Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
title Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
spellingShingle Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
Giménez Carabaza, Neus
Leucèmia limfocítica crònica
Mutació (Biologia)
Chronic lymphocytic leukemia
Mutation (Biology)
title_short Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
title_full Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
title_fullStr Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
title_full_unstemmed Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
title_sort Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
dc.creator.none.fl_str_mv Giménez Carabaza, Neus
Martínez Trillos, Alejandra
Montraveta, Arnau
López-Guerra, Mónica
Rosich, Laia
Nadeu Prat, Ferran
Valero, Juan G.
Aymerich Gregorio, Marta
Magnano, Laura
Rozman, María
Matutes, Estella
Delgado, Julio (Delgado González)
Baumann, Tycho
Giné Soca, Eva
González, Marcos
Alcoceba, Miguel
Terol, Maria José
Navarro, Blanca
Colado, Enrique
Payer, Ángel R.
Puente, Xose S.
López-Otin, Carlos
López Guillermo, Armando
Campo Güerri, Elias
Colomer Pujol, Dolors
Villamor i Casas, Neus
author Giménez Carabaza, Neus
author_facet Giménez Carabaza, Neus
Martínez Trillos, Alejandra
Montraveta, Arnau
López-Guerra, Mónica
Rosich, Laia
Nadeu Prat, Ferran
Valero, Juan G.
Aymerich Gregorio, Marta
Magnano, Laura
Rozman, María
Matutes, Estella
Delgado, Julio (Delgado González)
Baumann, Tycho
Giné Soca, Eva
González, Marcos
Alcoceba, Miguel
Terol, Maria José
Navarro, Blanca
Colado, Enrique
Payer, Ángel R.
Puente, Xose S.
López-Otin, Carlos
López Guillermo, Armando
Campo Güerri, Elias
Colomer Pujol, Dolors
Villamor i Casas, Neus
author_role author
author2 Martínez Trillos, Alejandra
Montraveta, Arnau
López-Guerra, Mónica
Rosich, Laia
Nadeu Prat, Ferran
Valero, Juan G.
Aymerich Gregorio, Marta
Magnano, Laura
Rozman, María
Matutes, Estella
Delgado, Julio (Delgado González)
Baumann, Tycho
Giné Soca, Eva
González, Marcos
Alcoceba, Miguel
Terol, Maria José
Navarro, Blanca
Colado, Enrique
Payer, Ángel R.
Puente, Xose S.
López-Otin, Carlos
López Guillermo, Armando
Campo Güerri, Elias
Colomer Pujol, Dolors
Villamor i Casas, Neus
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Leucèmia limfocítica crònica
Mutació (Biologia)
Chronic lymphocytic leukemia
Mutation (Biology)
topic Leucèmia limfocítica crònica
Mutació (Biologia)
Chronic lymphocytic leukemia
Mutation (Biology)
description Mutations in genes of the RAS-BRAF-MAPK-ERK pathwayhave not been fully explored in patients with chronic lym-phocytic leukemia. We, therefore, analyzed the clinical andbiological characteristics of chronic lymphocytic leukemia patientswith mutations in this pathway and investigated thein vitroresponseof primary cells to BRAF and ERK inhibitors. Putative damaging muta-tions were found in 25 of 452 patients (5.5%). Among these, BRAFwas mutated in nine patients (2.0%), genes upstream of BRAF(KITLG,KIT, PTPN11, GNB1, KRASand NRAS) were mutated in 12 patients(2.6%), and genes downstream of BRAF(MAPK2K1, MAPK2K2, andMAPK1) were mutated in five patients (1.1%). The most frequentmutations were missense, subclonal and mutually exclusive. Patientswith these mutations more frequently had increased lactate dehydro-genase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12and unmutated immunoglobulin heavy-chain variable region genesand had a worse 5-year time to first treatment (hazard ratio 1.8,P=0.025). Gene expression analysis showed upregulation of genes ofthe MAPK pathway in the group carrying RAS-BRAF-MAPK-ERKpathway mutations. The BRAF inhibitors vemurafenib and dabrafenibwere not able to inhibit phosphorylation of ERK, the downstreameffector of the pathway, in primary cells. In contrast, ulixertinib, apan-ERK inhibitor, decreased phospho-ERK levels. In conclusion,although larger series of patients are needed to corroborate these find-ings, our results suggest that the RAS-BRAF-MAPK-ERK pathway isone of the core cellular processes affected by novel mutations inchronic lymphocytic leukemia, is associated with adverse clinical fea-tures and could be pharmacologically inhibited.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
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 https://hdl.handle.net/2445/148047
url https://hdl.handle.net/2445/148047
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3324/haematol.2018.196931
Haematologica, 2019, vol. 104, num. 3, p. 576-586
https://doi.org/10.3324/haematol.2018.196931
info:eu-repo/grantAgreement/EC/FP7/306240
dc.rights.none.fl_str_mv (c) Ferrata Storti Foundation, 2018
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Ferrata Storti Foundation, 2018
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 11 p.
application/pdf
dc.publisher.none.fl_str_mv Ferrata Storti Foundation
publisher.none.fl_str_mv Ferrata Storti Foundation
dc.source.none.fl_str_mv Articles publicats en revistes (Fonaments Clínics)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869423161411371008
score 15,81155

Similares en LA Referencia