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


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.
Université Libre de Bruxelles, Institut Jules Bordet, Laboratoire d'Hématologie Expérimentale, Bruxelles, Belgium. bstamato@ulb.ac.be
Basile
B
Stamatopoulos
Benjamin
B
Haibe-Kains
Carole
C
Equeter
Nathalie
N
Meuleman
Anne
A
Sorée
Cécile
C
De Bruyn
Delphine
D
Hanosset
Dominique
D
Bron
Philippe
P
Martiat
Laurence
L
Lagneaux
D000368:Aged; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D016000:Cluster Analysis; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D037181:Lectins, C-Type; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000473:pathology; D016019:Survival Analysis; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics* / Q000378:metabolism; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099192:CD69 Antigens; C527276:CXCR4 protein, human; C497261:ZAP70 protein, human