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http://hdl.handle.net/2445/147935
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 Lymphomas 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: https://doi.org/10.3324/haematol.2017.180505 |
It is part of: | Haematologica, 2019, vol. 104, num. 4, p. 778-788 |
URI: | http://hdl.handle.net/2445/147935 |
Related resource: | https://doi.org/10.3324/haematol.2017.180505 |
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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