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Title: Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
Author: Recasens Zorzo, Clara
Cardesa Salzmann, Teresa
Petazzi, Paolo
Ros Blanco, Laia
Esteve Arenys, Anna
Clot, Guillem
Guerrero Hernández, Martina
Rodríguez, Vanina
Soldini, Davide
Valera Barros, Alexandra
Moros Sanz, Alexandra
Climent, Fina
González Barca, Eva
Mercadal, Santiago
Arenillas Rocha, Leonor
Calvo, Xavier
Mate, José L.
Gutiérrez García, Gonzalo
Casanova Rigat, Isolda
Mangues Bafalluy, Ramon
Sanjuan Pla, Alejandra
Bueno, Clara
Menéndez Buján, Pablo
Martínez, Antonio
Colomer Pujol, Dolors
Estrada Tejedor, Roger
Teixidó, Jordi
Campo Güerri, Elias
López Guillermo, Armando
Borrell, José Ignacio
Colomo Saperas, Lluís
Pérez Galán, Patricia
Roué, Gaël
Keywords: Limfomes
Cèl·lules B
B cells
Issue Date: 1-Apr-2019
Publisher: Ferrata Storti Foundation
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.
Note: Reproducció del document publicat a:
It is part of: Haematologica, 2019, vol. 104, num. 4, p. 778-788
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ISSN: 0390-6078
Appears in Collections:Articles publicats en revistes (Fonaments Clínics)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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