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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.
 Previous Article | Next Article 
Submitted June 4, 2007
Accepted August 10, 2007
CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential
Silvia Deaglio, Tiziana Vaisitti, Semra Aydin, Luciana Bergui, Giovanni D'Arena, Lisa Bonello, Paola Omede', Maria Scatolini, Ozren Jaksic, Giovanna Chiorino, Dimitar Efremov, and Fabio Malavasi*
Dept of Genetics, Biology and Biochemistry, University of Torino Medical School, Turin, Italy
Department of Medicine and Experimental Oncology, University of Torino Medical School, Turin, Italy
IRCCS Fondazione G. Pascale, Naples, Italy
Research Center for Experimental Medicine, University of Torino Medical School, Turin, Italy
Fondo Edo Tempia, Biella, Italy
Department of Hematology, Merkur University Hospital, Zagreb, Croatia
ICGEB Outstation-Monterotondo, CNR Campus "Adriano Buzzati Traverso", Rome, Italy
Department of Biology, Genetics and Biochemistry, University of Torino Medical School, Turin, Italy
* Corresponding author; email: fabio.malavasi{at}unito.it.
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 clinically and molecularly characterized CLL patients, we show that i) CD38+/ZAP-70+ patients are characterized by enhanced migration towards SDF-1  /CXCL12. Further, ii) CD38 ligation leads to tyrosine phosphorylation of ZAP-70, showing that these markers are functionally linked. Thirdly, iii) 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. Lastly, iv) 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 CLL patients with aggressive disease.
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