Page 150 - 2019_04-Haematologica-web

Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):778-788
Non-Hodgkin Lymphoma
Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
1Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona; 2Hematopathology Unit, Department of Pathology, Hospital Clinic, Barcelona; 3Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona; 4Grup d’Enginyeria Molecular, IQS School of Engineering, Universitat Ramon Llull, Barcelona; 5Pathology Department, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat; 6Institut Catalá d’Oncología, Hospital Duran I Reynals, L’Hospitalet de Llobregat; 7Pathology Department, IMIM, Hospital del Mar, Barcelona; 8Pathology Department, Hospital Universitari Germans Trias i Pujol, Badalona; 9Department of Hematology, Hospital Clinic, Barcelona; 10Grup d’Oncogènesi i Antitumorals, lnstitut d’Investigacions Biomèdiques Sant Pau (IIB-Sant Pau) and Centro de Investigación Biomédica en Red CIBER-BBN, Barcelona; 11Hematology Research Group, Health Research Institute La Fe, Valencia; 12Institucio Catalana de Recerca I Estudis Avançats (ICREA), CIBERONC, Barcelona and 13Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain
LC, PP-G and GR. share senior authorship.
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 prognos- tic 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 lev- els of CXCL12 correlated with high microvessel density and bone mar- row 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, allow- ing 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 lym- phoma and support the simultaneous targeting of CXCR4 and bromod- omain proteins as a promising, rationale-based strategy for the treatment of this disease.
Clara Recasens-Zorzo,1 Teresa Cardesa-Salzmann,2 Paolo Petazzi,3
Laia Ros-Blanco,4 Anna Esteve-Arenys,1 Guillem Clot,1
Martina Guerrero-Hernández,1 Vanina Rodríguez,1 Davide Soldini,2 Alexandra Valera,2 Alexandra Moros,1 Fina Climent,5 Eva González-Barca,6 Santiago Mercadal,6 Leonor Arenillas,7 Xavier Calvo,7 José Luís Mate,8
9 3,10 3,10 Gonzalo Gutiérrez-García, Isolda Casanova, Ramón Mangues,
Alejandra Sanjuan-Pla,
Antonio Martínez,1,2 Dolors Colomer,1,2 Roger Estrada Tejedor,4 Jordi Teixidó,4 Elias Campo,1,2 Armando López-Guillermo,1,9 José Ignacio Borrell,4
Luis Colomo,2,7 Patricia Pérez-Galán1 and Gaël Roué1,13
11 3
Clara Bueno, Pablo Menéndez,
3,12
Correspondence:
GAËL ROUÉ
groue@vhebron.net
PATRICIA PÉREZ-GALÁN
pperez@clinic.ub.es
Received: September 8, 2017. Accepted: June 25, 2018. Pre-published: June 28, 2018.
doi:10.3324/haematol.2017.180505
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/778
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
778
haematologica | 2019; 104(4)
ARTICLE