The VLA-4 integrin is constitutively active in circulating chronic lymphocytic leukemia cells via BCR autonomous signaling: a novel anchor-independent mechanism exploiting soluble blood-borne ligands.

Autor: Tissino E; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy. etissino@cro.it., Gaglio A; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Nicolò A; Institut für Immunologie, Universitätsklinikum Ulm, Ulm, Germany., Pozzo F; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Bittolo T; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Rossi FM; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Bomben R; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Nanni P; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Cattarossi I; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Zaina E; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Zimbo AM; Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.; Haematology Unit, Azienda Ospedaliera Annunziata, Cosenza, Italy., Ianna G; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Capasso G; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Forestieri G; Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland., Moia R; Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy., Datta M; Institut für Immunologie, Universitätsklinikum Ulm, Ulm, Germany., Härzschel A; Department of Internal Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Olivieri J; Clinica Ematologica, Centro Trapianti e Terapie Cellulari 'Carlo Melzi' DISM, Azienda Ospedaliera Universitaria S. Maria Misericordia, Udine, Italy., D'Arena G; Hematology, 'S. Luca' Hospital, ASL Salerno, Vallo della Lucania, Italy., Laurenti L; Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy., Zaja F; Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy., Chiarenza A; Division of Hematology, Ferrarotto Hospital, University of Catania, Catania, Italy., Palumbo GA; Dipartimento di Scienze Mediche, Chirurgiche e Tecnologie Avanzate 'G.F. Ingrassia', University of Catania, Catania, Italy., Martino EA; Haematology Unit, Azienda Ospedaliera Annunziata, Cosenza, Italy., Gentile M; Haematology Unit, Azienda Ospedaliera Annunziata, Cosenza, Italy.; Department of Pharmacy, Health and Nutritional Science, University of Calabria, Rende, Italy., Rossi D; Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland., Gaidano G; Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy., Del Poeta G; Division of Hematology, University of Tor Vergata, Rome, Italy., Laureana R; Division of Hematology, University of Tor Vergata, Rome, Italy., Del Principe MI; Division of Hematology, University of Tor Vergata, Rome, Italy., Maity PC; Institut für Experimentelle Tumorforschung, Universitätsklinikum Ulm, Ulm, Germany., Jumaa H; Institut für Immunologie, Universitätsklinikum Ulm, Ulm, Germany., Hartmann TN; Department of Internal Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Zucchetto A; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy. zucchetto.soecs@cro.it., Gattei V; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy. vgattei@cro.it.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2024 Oct; Vol. 38 (10), pp. 2127-2140. Date of Electronic Publication: 2024 Aug 14.
DOI: 10.1038/s41375-024-02376-7
Abstrakt: In chronic lymphocytic leukemia (CLL), survival of neoplastic cells depends on microenvironmental signals at lymphoid sites where the crosstalk between the integrin VLA-4 (CD49d/CD29), expressed in ~40% of CLL, and the B-cell receptor (BCR) occurs. Here, BCR engagement inside-out activates VLA-4, thus enhancing VLA-4-mediated adhesion of CLL cells, which in turn obtain pro-survival signals from the surrounding microenvironment. We report that the BCR is also able to effectively inside-out activate the VLA-4 integrin in circulating CD49d-expressing CLL cells through an autonomous antigen-independent BCR signaling. As a consequence, circulating CLL cells exhibiting activated VLA-4 express markers of BCR pathway activation (phospho-BTK and phospho-PLC-γ2) along with higher levels of phospho-ERK and phospho-AKT indicating parallel activation of downstream pathways. Moreover, circulating CLL cells expressing activated VLA-4 bind soluble blood-borne VCAM-1 leading to increased VLA-4-dependent actin polymerization/re-organization and ERK phosphorylation. Finally, evidence is provided that ibrutinib treatment, by affecting autonomous BCR signaling, impairs the constitutive VLA-4 activation eventually decreasing soluble VCAM-1 binding and reducing downstream ERK phosphorylation by circulating CLL cells. This study describes a novel anchor-independent mechanism occurring in circulating CLL cells involving the BCR and the VLA-4 integrin, which help to unravel the peculiar biological and clinical features of CD49d+ CLL.
(© 2024. The Author(s).)
Databáze: MEDLINE
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