Variability in the degree of expression of phosphorylated IkappaBalpha in chronic lymphocytic leukemia cases with nodal involvement.

Abstract

Based on previous preliminary observations, we hypothesize that the molecular and clinical variability of chronic lymphocytic leukemia (CLL) reflects differences in the degree of nuclear factor (NF)-kappaB activation, as determined by the expression of phosphorylated IkappaBalpha (p-IkappaBalpha). The expression profile (mRNA and protein expression) was analyzed with the Centro Nacional de Investigaciones Oncologicas Oncochip, a cDNA microarray containing 6386 cancer-related genes, and a tissue microarray (TMA). The results were correlated with the IgV(H) mutational status, ZAP-70 expression, cytogenetic alterations, and clinical outcome. We found correlations between the presence of p-IkappaBalpha, a surrogate marker of NF-kappaB activation, and changes in the expression profile (mRNA and protein expression) and clinical outcome in a series of CLL cases with lymph node involvement. Activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, was associated with the expression of a set of genes comprising key genes involved in the control of B-cell receptor signaling, signal transduction, and apoptosis, including SYK, LYN, BCL2, CCR7, BTK, PIK3CD, and others. Cases with increased expression of p-IkappaBalpha showed longer overall survival than cases with lower expression. A Cox regression model was derived to estimate some parameters of prognostic interest: IgV(H) mutational status, ZAP-70, and p-IkappaBalpha expression. The multivariate analysis disclosed p-IkappaBalpha and ZAP-70 expression as independent prognostic factors of survival. A variable degree of activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, is an identifiable event in CLL, and is correlated with changes in the expression profile and overall survival.