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.