Published online 18 April 2009
Haematologica, Vol 94, Issue 6, 790-799 doi:10.3324/haematol.2008.002626
Copyright © 2009 by Ferrata Storti Foundation

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Original Article

Gene expression profiling reveals differences in microenvironment interaction between patients with chronic lymphocytic leukemia expressing high versus low ZAP70 mRNA

Basile Stamatopoulos¹, Benjamin Haibe-Kains^2,3, Carole Equeter², Nathalie Meuleman¹, Anne Sorée¹, Cécile De Bruyn¹, Delphine Hanosset¹, Dominique Bron¹, Philippe Martiat¹, Laurence Lagneaux¹

¹ Laboratory of Experimental Hematology, Faculty of Medicine, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels
² Functional Genomics and Translational Research Unit, Faculty of Medicine, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels
³ Machine Learning Group, Faculty of Sciences, Université Libre de Bruxelles (ULB), Brussels, Belgium

Correspondence: Basile Stamatopoulos, Université Libre de Bruxelles, Institut Jules Bordet, Laboratoire d'Hématologie Expérimentale, Boulevard de Waterloo 121, 1000 Bruxelles, Belgium., E-mail:bstamato{at}ulb.ac.be

Background: Zeta-associated protein 70 (ZAP70) is a widely recognized prognostic factor in chronic lymphocytic leukemia, but mechanisms by which its higher expression leads to a poor outcome must still be fully explained.

Design and Methods: In an attempt to unveil unfavorable cellular properties linked to high ZAP70 expression, we used gene expression profiling to identify genes associated with disparities in B cells from chronic lymphocytic leukemia patients expressing high versus low ZAP70 mRNA, measured by quantitative real-time PCR. Two groups of 7 patients were compared, selected on the basis of either high or low ZAP70 mRNA expression.

Results: Twenty-seven genes were differentially expressed with an FDR<10%, and several genes were significant predictors of treatment-free survival (TFS) and/or overall survival; PDE8A and FCRL family genes (down-regulated in ZAP70⁺ patients) could predict TFS and overall survival; ITGA4 mRNA (up-regulated in ZAP70⁺ patients) could significantly predict overall survival. Importantly, gene set enrichment analysis revealed overrepresentation of adhesion/migration genes. We therefore investigated in vitro adhesion/migration capacity of chronic lymphocytic leukemia cells into a stromal microenvironment or in response to conditioned medium. We showed that ZAP70⁺ cells had better adhesion/migration capacities and only ZAP70⁺ patient cells responded to microenvironment contact by CXCR4 downregulation.

Conclusions: We concluded that several prognostic factors are the reflection of microenvironment interactions and that the increased adhesion/migratory capacity of ZAP70⁺ cells in their microenvironment can explain their better survival and thus the aggressiveness of the disease.

Key words: chronic lymphocytic leukemia, ZAP70, microarrays, microenvironment, prognosis.

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