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Blood, 1 December 2007, Vol. 110, No. 12, pp. 4012-4021.
Prepublished online as a Blood First Edition Paper on August 15, 2007; DOI 10.1182/blood-2007-06-094029.
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NEOPLASIA
CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential
Silvia Deaglio1,2,
Tiziana Vaisitti1,2,
Semra Aydin1,2,
Luciana Bergui3,
Giovanni D'Arena4,
Lisa Bonello2,
Paola Omedé3,
Maria Scatolini5,
Ozren Jaksic6,
Giovanna Chiorino5,
Dimitar Efremov7, and
Fabio Malavasi1,2
1 Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Turin, Italy;
2 Research Center for Experimental Medicine (CeRMS), University of Torino Medical School, Turin, Italy;
3 Department of Medicine and Experimental Oncology, University of Torino Medical School, Turin, Italy;
4 Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G. Pascale, Naples, Italy;
5 Fondo Edo Tempia, Biella, Italy;
6 Department of Hematology, Merkur University Hospital, Zagreb, Croatia; and
7 International Centre for Genetic Engineering and Biotechnology (ICGEB) Outstation—Monterotondo, Consiglio Nazionale delle Ricerche (CNR) Campus Adriano Buzzati-Traverso, Rome, Italy
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 nurselike 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-1 (SDF-1)/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.
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