Gene
expression comparison between B cells expressing high and low level of
Zap-70 mRNA reveals distinct profiles, potential therapeutic targets
and new prognostic factors for Chronic Lymphocytic Leukemia
Stamatopoulos B, Equeter C, Haibe-Kains B, Soree A, Sotiriou C, Bron D, Martiat P, Lagneaux L
Background: Chronic Lymphocytic
Leukemia (CLL) is a heterogeneous disease characterized by a highly
variable clinical course based on the IgVH mutational status currently
considered as one of the powerful prognosis factors. Because of the
complexity of this analysis, several surrogate genes of this mutational
status have been found in the recent years, among them Zap-70 seems to
be a reliable prognostic factor.
Methods: We compared three
predictive markers (Zap-70, lipoprotein lipase and CD38 expression) in
term of treatment-free (TFS) and overall (OS) survival and finally
Zap-70 (zeta-associated protein 70) was chosen because of its strong
association with the IgVH status and high prognostic values. We
developed a quantitative real time PCR to measure Zap-70 mRNA
expression in a cohort of 100 patients and to classify patients with
high and low Zap-70 expression. Gene expression profiles of high
(Zap-70high, n=7) and low (Zap-70low, n=7) mRNA expression were then
compared using Affymetrix U133 plus 2.0 genechips representing more
than 47000 transcripts.
Results: Among genes
differently expressed (P<0.05), only genes with a fold change upper
of 1.5 and with a false discovery rate (FDR) lower than 10% were
selected. Zap-70, the first gene of the list, was followed by the
phosphodiesterase 8A (PDE8A, P<0.0001), integrin alpha 4 (ITGA4,
P<0.0001) and some genes of Fc receptor like family (FCRL,
P<0.0001). These genes were confirmed in an extended patient cohort
(n=80) and were able to separate the patients in term of TFS indicating
their relevant clinical predictive power.
Conclusion: CLL cells
expressing high and low level of Zap-70 mRNA are characterized by a
distinct gene expression profile that reveals new potential therapeutic
target, new prognostic factors and genes implicated in cellular
activation, adhesion and migration.