title: CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential.
abstract: 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.
authors: Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Turin, Italy. silvia.deaglio@unito.it
authors: Silvia
authors: S
authors: Deaglio
authors: Tiziana
authors: T
authors: Vaisitti
authors: Semra
authors: S
authors: Aydin
authors: Luciana
authors: L
authors: Bergui
authors: Giovanni
authors: G
authors: D'Arena
authors: Lisa
authors: L
authors: Bonello
authors: Paola
authors: P
authors: Omedé
authors: Maria
authors: M
authors: Scatolini
authors: Ozren
authors: O
authors: Jaksic
authors: Giovanna
authors: G
authors: Chiorino
authors: Dimitar
authors: D
authors: Efremov
authors: Fabio
authors: F
authors: Malavasi
mesh_terms: 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*
chemical_list: 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