Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells

Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell p...

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Autores: López-Guerra, Mónica, Xargay i Torrent, Sílvia, Fuentes, Patricia, Roldán, Jocabed, González Farré, Blanca, Rosich, Laia, Silkenstedt, Elisabeth, García León, María J., Lee-Vergés, Eriong, Giménez Carabaza, Neus, Giró, Ariadna, Aymerich Gregorio, Marta, Villamor i Casas, Neus, Delgado, Julio (Delgado González), López Guillermo, Armando, Puente, Xose S., Campo Güerri, Elias, Toribio, María L., Colomer Pujol, Dolors
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/172249
Acceso en línea:https://hdl.handle.net/2445/172249
Access Level:acceso abierto
Palabra clave:Leucèmia limfocítica crònica
Angiogènesi
Chronic lymphocytic leukemia
Neovascularization
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spelling Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cellsLópez-Guerra, MónicaXargay i Torrent, SílviaFuentes, PatriciaRoldán, JocabedGonzález Farré, BlancaRosich, LaiaSilkenstedt, ElisabethGarcía León, María J.Lee-Vergés, EriongGiménez Carabaza, NeusGiró, AriadnaAymerich Gregorio, MartaVillamor i Casas, NeusDelgado, Julio (Delgado González)López Guillermo, ArmandoPuente, Xose S.Campo Güerri, EliasToribio, María L.Colomer Pujol, DolorsLeucèmia limfocítica crònicaAngiogènesiChronic lymphocytic leukemiaNeovascularizationTargeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.Macmillan Publishers2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/172249Articles publicats en revistes (Fonaments Clínics)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/s41388-019-1053-6Oncogene, 2019, vol. 39, p. 1185-1197https://doi.org/10.1038/s41388-019-1053-6cc by (c) Macmillan Publishers, 2019http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1722492026-05-27T06:46:51Z
dc.title.none.fl_str_mv Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells
title Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells
spellingShingle Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells
López-Guerra, Mónica
Leucèmia limfocítica crònica
Angiogènesi
Chronic lymphocytic leukemia
Neovascularization
title_short Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells
title_full Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells
title_fullStr Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells
title_full_unstemmed Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells
title_sort Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells
dc.creator.none.fl_str_mv López-Guerra, Mónica
Xargay i Torrent, Sílvia
Fuentes, Patricia
Roldán, Jocabed
González Farré, Blanca
Rosich, Laia
Silkenstedt, Elisabeth
García León, María J.
Lee-Vergés, Eriong
Giménez Carabaza, Neus
Giró, Ariadna
Aymerich Gregorio, Marta
Villamor i Casas, Neus
Delgado, Julio (Delgado González)
López Guillermo, Armando
Puente, Xose S.
Campo Güerri, Elias
Toribio, María L.
Colomer Pujol, Dolors
author López-Guerra, Mónica
author_facet López-Guerra, Mónica
Xargay i Torrent, Sílvia
Fuentes, Patricia
Roldán, Jocabed
González Farré, Blanca
Rosich, Laia
Silkenstedt, Elisabeth
García León, María J.
Lee-Vergés, Eriong
Giménez Carabaza, Neus
Giró, Ariadna
Aymerich Gregorio, Marta
Villamor i Casas, Neus
Delgado, Julio (Delgado González)
López Guillermo, Armando
Puente, Xose S.
Campo Güerri, Elias
Toribio, María L.
Colomer Pujol, Dolors
author_role author
author2 Xargay i Torrent, Sílvia
Fuentes, Patricia
Roldán, Jocabed
González Farré, Blanca
Rosich, Laia
Silkenstedt, Elisabeth
García León, María J.
Lee-Vergés, Eriong
Giménez Carabaza, Neus
Giró, Ariadna
Aymerich Gregorio, Marta
Villamor i Casas, Neus
Delgado, Julio (Delgado González)
López Guillermo, Armando
Puente, Xose S.
Campo Güerri, Elias
Toribio, María L.
Colomer Pujol, Dolors
author2_role 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
Angiogènesi
Chronic lymphocytic leukemia
Neovascularization
topic Leucèmia limfocítica crònica
Angiogènesi
Chronic lymphocytic leukemia
Neovascularization
description Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.
publishDate 2019
dc.date.none.fl_str_mv 2019
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/2445/172249
url https://hdl.handle.net/2445/172249
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/10.1038/s41388-019-1053-6
Oncogene, 2019, vol. 39, p. 1185-1197
https://doi.org/10.1038/s41388-019-1053-6
dc.rights.none.fl_str_mv cc by (c) Macmillan Publishers, 2019
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Macmillan Publishers, 2019
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Macmillan Publishers
publisher.none.fl_str_mv Macmillan Publishers
dc.source.none.fl_str_mv Articles publicats en revistes (Fonaments Clínics)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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