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.
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.
Zucchetto
Antonella
A
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
Benedetti
Dania
D
Tripodo
Claudio
C
Bomben
Riccardo
R
Dal Bo
Michele
M
Marconi
Daniela
D
Bossi
Fleur
F
Lorenzon
Debora
D
Degan
Massimo
M
Rossi
Francesca Maria
FM
Rossi
Davide
D
Bulian
Pietro
P
Franco
Vito
V
Del Poeta
Giovanni
G
Deaglio
Silvia
S
Gaidano
Gianluca
G
Tedesco
Francesco
F
Malavasi
Fabio
F
Gattei
Valter
V
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*
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