Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
Recasens-Zorzo, Clara (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Cardesa-Salzmann, Teresa (Hospital Clínic i Provincial de Barcelona)
Petazzi, Paolo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ros-Blanco, Laia (Universitat Ramon Llull. Institut Químic de Sarrià-IQS)
Esteve-Arenys, Anna (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Clot, Guillem (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Guerrero-Hernández, Martina (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Rodríguez, Vanina (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Soldini, Davide (Hospital Clínic i Provincial de Barcelona)
Valera, Alexandra (Hospital Clínic i Provincial de Barcelona)
Moros, Alexandra (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Climent, Fina (Hospital Universitari de Bellvitge)
Gonzalez-Barca, Eva (Institut Català d'Oncologia)
Mercadal, Santiago (Institut Català d'Oncologia)
Arenillas, Leonor (Institut Hospital del Mar d'Investigacions Mèdiques)
Calvo, Xavier (Institut Hospital del Mar d'Investigacions Mèdiques)
Mate Sanz, Jose Luís (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Gutiérrez-García, Gonzalo (Hospital Clínic i Provincial de Barcelona)
Casanova Rigat, Isolda (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Mangues, Ramon 1957- (Institut d'Investigació Biomèdica Sant Pau)
Sanjuan-Pla, Alejandra (Hospital Universitari i Politècnic La Fe (València))
Bueno, Clara (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Menéndez Bujan, Pablo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Martínez, Antonio (Hospital Clínic i Provincial de Barcelona)
Colomer, Dolors (Hospital Clínic i Provincial de Barcelona)
Estrada Tejedor, Roger (Universitat Ramon Llull)
Teixidó, Jordi (Universitat Ramon Llull)
Campo, Elias (Hospital Clínic i Provincial de Barcelona)
López-Guillermo, A. (Hospital Clínic i Provincial de Barcelona)
Borrell, José Ignacio (Universitat Ramon Llull)
Colomo, Luis (Institut Hospital del Mar d'Investigacions Mèdiques)
Pérez-Galán, Patricia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Roué, Gaël (Vall d'Hebron Institut d'Oncologia)
Universitat Autònoma de Barcelona

Date:	2019
Abstract:	Constitutive activation of the chemokine receptor CXCR4 has been 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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Acetamides ; Animals ; Azepines ; Biopsy ; Cell Line, Tumor ; Cemokine CXCL12 ; Female ; Humans ; Lymphoma, Large B-Cell, Diffuse ; MAP Kinase Signaling System ; Male ; Mice ; Mitogen-Activated Protein Kinase 1 ; Mitogen-Activated Protein Kinase 3 ; Proto-Oncogene Proteins c-akt ; Receptors, CXCR4 ; Xenograft Model Antitumor Assays
Published in:	Haematologica, Vol. 104 Núm. 4 (31 2019) , p. 778-788, ISSN 1592-8721

DOI: 10.3324/haematol.2017.180505
PMID: 29954928

11 p, 1.9 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Social and Legal Sciences > The Department of Communication and Education
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles