title: CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival.
abstract: CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38(+)CD49d(+) versus CD38(-)CD49d(-) CLL cells, we showed overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also up-regulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38(+)CD49d(+) but not CD38(-)CD49d(-) cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68(+) macrophage infiltration was particularly high in BMB from CD38(+)CD49d(+) CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express vascular cell adhesion molecule-1 (VCAM-1), the CD49d ligand, likely through tumor necrosis factor alpha overproduction. These effects were apparent in BMB from CD38(+)CD49d(+) CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1(+) stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1 transfectants increased viability of CD38(+)CD49d(+) CLL cells. Altogether, CD38 and CD49d can be thought of as parts of a consecutive chain of events ultimately leading to improved survival of CLL cells.
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Zucchetto
authors.forename: Dania
authors.initials: D
authors.lastname: Benedetti
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bomben
authors.forename: Michele
authors.initials: M
authors.lastname: Dal Bo
authors.forename: Daniela
authors.initials: D
authors.lastname: Marconi
authors.forename: Fleur
authors.initials: F
authors.lastname: Bossi
authors.forename: Debora
authors.initials: D
authors.lastname: Lorenzon
authors.forename: Massimo
authors.initials: M
authors.lastname: Degan
authors.forename: Francesca Maria
authors.initials: FM
authors.lastname: Rossi
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Pietro
authors.initials: P
authors.lastname: Bulian
authors.forename: Vito
authors.initials: V
authors.lastname: Franco
authors.forename: Giovanni
authors.initials: G
authors.lastname: Del Poeta
authors.forename: Silvia
authors.initials: S
authors.lastname: Deaglio
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Francesco
authors.initials: F
authors.lastname: Tedesco
authors.forename: Fabio
authors.initials: F
authors.lastname: Malavasi
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D054405:Chemokine CCL3 / Q000096:biosynthesis / Q000276:immunology*; D054407:Chemokine CCL4 / Q000096:biosynthesis / Q000276:immunology*; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D039441:Integrin alpha4 / Q000096:biosynthesis / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D015703:Antigens, CD; C515429:CCL3 protein, human; C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019707:Receptors, Chemokine; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1