Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma

Constitutive activation of the chemokine receptor CXCR4 has be en associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biolog...

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Autores: Recasens-Zorzo, C, Cardesa-Salzmann, T, Petazzi, P, Ros-Blanco, L, Esteve-Arenys, A, Clot, G, Guerrero-Hernandez, M, Rodriguez, V, Soldini, D, Valera, A, Moros, A, Climent, F, Gonzalez-Barca, E, Mercadal, S, Arenillas, L, Calvo, X, Mate, JL, Gutierrez-Garcia, G, Casanova, I, Mangues, R, Sanjuan-Pla, A, Bueno, C, Menendez, P, Martinez, A, Colomer, D, Tejedor, RE, Teixido, J, Campo, E, Lopez-Guillermo, A, Borrell, JI, Colomo, L, Perez-Galan, P, Roui, G
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p2888
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2888
http://ddd.uab.cat/record/236800
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spelling Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphomaRecasens-Zorzo, CCardesa-Salzmann, TPetazzi, PRos-Blanco, LEsteve-Arenys, AClot, GGuerrero-Hernandez, MRodriguez, VSoldini, DValera, AMoros, ACliment, FGonzalez-Barca, EMercadal, SArenillas, LCalvo, XMate, JLGutierrez-Garcia, GCasanova, IMangues, RSanjuan-Pla, ABueno, CMenendez, PMartinez, AColomer, DTejedor, RETeixido, JCampo, ELopez-Guillermo, ABorrell, JIColomo, LPerez-Galan, PRoui, GConstitutive activation of the chemokine receptor CXCR4 has be en associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.FERRATA STORTI FOUNDATION2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2888http://ddd.uab.cat/record/236800HAEMATOLOGICAISSN: 07182295ISSNe: 15928721ISSNl: 03906078reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p28882026-06-14T12:41:47Z
dc.title.none.fl_str_mv Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
title Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
spellingShingle Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
Recasens-Zorzo, C
title_short Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
title_full Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
title_fullStr Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
title_full_unstemmed Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
title_sort Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
dc.creator.none.fl_str_mv Recasens-Zorzo, C
Cardesa-Salzmann, T
Petazzi, P
Ros-Blanco, L
Esteve-Arenys, A
Clot, G
Guerrero-Hernandez, M
Rodriguez, V
Soldini, D
Valera, A
Moros, A
Climent, F
Gonzalez-Barca, E
Mercadal, S
Arenillas, L
Calvo, X
Mate, JL
Gutierrez-Garcia, G
Casanova, I
Mangues, R
Sanjuan-Pla, A
Bueno, C
Menendez, P
Martinez, A
Colomer, D
Tejedor, RE
Teixido, J
Campo, E
Lopez-Guillermo, A
Borrell, JI
Colomo, L
Perez-Galan, P
Roui, G
author Recasens-Zorzo, C
author_facet Recasens-Zorzo, C
Cardesa-Salzmann, T
Petazzi, P
Ros-Blanco, L
Esteve-Arenys, A
Clot, G
Guerrero-Hernandez, M
Rodriguez, V
Soldini, D
Valera, A
Moros, A
Climent, F
Gonzalez-Barca, E
Mercadal, S
Arenillas, L
Calvo, X
Mate, JL
Gutierrez-Garcia, G
Casanova, I
Mangues, R
Sanjuan-Pla, A
Bueno, C
Menendez, P
Martinez, A
Colomer, D
Tejedor, RE
Teixido, J
Campo, E
Lopez-Guillermo, A
Borrell, JI
Colomo, L
Perez-Galan, P
Roui, G
author_role author
author2 Cardesa-Salzmann, T
Petazzi, P
Ros-Blanco, L
Esteve-Arenys, A
Clot, G
Guerrero-Hernandez, M
Rodriguez, V
Soldini, D
Valera, A
Moros, A
Climent, F
Gonzalez-Barca, E
Mercadal, S
Arenillas, L
Calvo, X
Mate, JL
Gutierrez-Garcia, G
Casanova, I
Mangues, R
Sanjuan-Pla, A
Bueno, C
Menendez, P
Martinez, A
Colomer, D
Tejedor, RE
Teixido, J
Campo, E
Lopez-Guillermo, A
Borrell, JI
Colomo, L
Perez-Galan, P
Roui, G
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
author
author
author
author
author
author
author
description Constitutive activation of the chemokine receptor CXCR4 has be en associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.
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://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2888
http://ddd.uab.cat/record/236800
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2888
http://ddd.uab.cat/record/236800
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv FERRATA STORTI FOUNDATION
publisher.none.fl_str_mv FERRATA STORTI FOUNDATION
dc.source.none.fl_str_mv HAEMATOLOGICA
ISSN: 07182295
ISSNe: 15928721
ISSNl: 03906078
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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