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

Stamatopoulos B, Haibe-Kains B, Equeter C, Meuleman N, Sorée A, De Bruyn C, Hanosset D, Bron D, Martiat P and Lagneaux L

Background: Zeta-associated protein 70 (ZAP70) is a widely recognized prognostic factor in chronic lymphocytic leukemia (CLL), but mechanisms by which its higher expression leads to a poor outcome remain to 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 CLL patients expressing high versus low ZAP70 mRNA, measured by quantitative real-time PCR. Two groups of seven 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 (OS);  PDE8A and FCRL family genes (downregulated in ZAP70+ patients) could predict TFS and OS; ITGA4 mRNA (upregulated in ZAP70+ patients) could significantly predict OS. Importantly, gene set enrichment analysis revealed overrepresentation of adhesion/migration genes. We therefore investigated in vitro adhesion/migration capacity of CLL 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.