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

Abstract

The online version of this article contains a supplementary appendix.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 MethodsIn 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. ResultsTwenty-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. ConclusionsWe 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.Citation: Stamatopoulos B, Haibe-Kains B, Equeter C, Meuleman N, Sorée A, De Bruyn C, Hanosset D, Bron D, Martiat P, and Lagneaux L. Gene expression profiling reveals differences in microenvironment interaction between patients with chronic lymphocytic leukemia expressing high versus low ZAP70 mRNA. Haematologica 2009; 94:790-799. doi:10.3324/haematol.2008 This is an open-access paper.Gene expression profiling reveals differences in microenvironment interaction between patients with chronic lymphocytic leukemia expressing high versus low ZAP70 mRNA

An eight-gene expression signature for the prediction of survival and time to treatment in chronic lymphocytic leukemia

“…Low transcript levels of the phosphodiesterase 8A (PDE8A) were associated with poor prognosis in our CLL patients. A similar association was reported by Stamatopoulos et al, 8 who showed that PDE8A was part of a gene signature that distinguishes between ZAP70 positive and ZAP70 negative CLL samples. PDE8A might be connected to the NF-kB signaling pathway, which is frequently activated in lymphoid malignancies.…”

Development and characterization of a physiologically relevant model of lymphocyte migration in chronic lymphocytic leukemia

“…42 CD69 has been shown to be a strong predictor of CLL prognosis and to be upregulated by microenvironmental contact. 5,11 The increase in expression of these markers on CLL cells under shear force implicates the action of shear force in the control of expression of these regulators of CLL cell motility.…”

“…In keeping with this concept, gene expression profiling revealed that increased expression of genes that code for proteins involved in the control of cell movement were correlated with poor prognosis. 11,12 One such protein, CD49d, which interacts with vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells during the process of CLL cell migration, has emerged as an important modulator of the pathology of CLL, as evidenced by the fact that it is an independent prognostic marker in this disease. [13][14][15] Here we describe the development and characterization of a novel circulating model system designed to investigate the interactions of CLL cells and endothelial cells under physiologically relevant shear forces.…”

The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis, down-regulates the CXCR4 chemokine receptor and impairs migration of chronic lymphocytic leukemia cells

“…30 Cells were pre-incubated alone or with SAHA for 24 h before performing the migration assay. Additional details are provided in the Online Supplementary Appendix.…”