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Haematologica. 2019 Apr;104(4):778-788. doi: 10.3324/haematol.2017.180505. Epub 2018 Jun 28.

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

Author information

1
Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona.
2
Hematopathology Unit, Department of Pathology, Hospital Clinic, Barcelona.
3
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona.
4
Grup d'Enginyeria Molecular, IQS School of Engineering, Universitat Ramon Llull, Barcelona.
5
Pathology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat.
6
Institut Catalá d'Oncología, Hospital Duran I Reynals, L'Hospitalet de Llobregat.
7
Pathology Department, IMIM, Hospital del Mar, Barcelona.
8
Pathology Department, Hospital Universitari Germans Trias i Pujol, Badalona.
9
Department of Hematology, Hospital Clinic, Barcelona.
10
Grup d'Oncogènesi i Antitumorals, lnstitut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau) and Centro de Investigación Biomédica en Red CIBER-BBN, Barcelona.
11
Hematology Research Group, Health Research Institute La Fe, Valencia.
12
Institucio Catalana de Recerca I Estudis Avançats (ICREA), CIBERONC, Barcelona.
13
Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona pperez@clinic.ub.es.
14
Division of Hemato-Oncology, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), CIBERONC, Barcelona groue@vhebron.net.
15
Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.

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.

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