CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential.
Our interest in chronic lymphocytic leukemia (CLL) derives primarily from the exploitation of human diseases as strategic models for defining the in vivo biological roles of CD38. Using this model, we showed that CD38 triggers robust proliferation/survival signals modulated through the interactions with the CD31 ligand expressed by nurse-like cells and by the stromal/endothelial components. By analyzing a cohort of 56 patients with clinically and molecularly characterized CLL, we show that (1) patients with CD38(+)/ZAP-70(+) are characterized by enhanced migration toward Stromal derived factor-1alpha (SDF-1alpha)/CXCL12; (2) CD38 ligation leads to tyrosine phosphorylation of ZAP-70, showing that these markers are functionally linked; (3) ZAP-70 represents a limiting factor for the CD38 pathway in the CLL context, as shown by studying CD38-mediated signal transduction in 26 molecularly characterized patients; and (4) the CLL subgroup of patients defined on the basis of migratory potential is marked by a specific genetic signature, with a significant number of differentially expressed genes being involved in cell-cell interactions and movement. Altogether, the results of this work provide biological evidence for why the combined analysis of CD38 and ZAP-70 expression as determined in several clinical trials results in more dependable identification of patients with CLL who have aggressive disease.
Deaglio
Silvia
S
Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Turin, Italy. silvia.deaglio@unito.it
Vaisitti
Tiziana
T
Aydin
Semra
S
Bergui
Luciana
L
D'Arena
Giovanni
G
Bonello
Lisa
L
Omedé
Paola
P
Scatolini
Maria
M
Jaksic
Ozren
O
Chiorino
Giovanna
G
Efremov
Dimitar
D
Malavasi
Fabio
F
D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D054377:Chemokine CXCL12 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015331:Cohort Studies; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology / Q000378:metabolism*
D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051746:ZAP-70 Protein-Tyrosine Kinase; D051997:ADP-ribosyl Cyclase 1