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

Abstract

Purpose: 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)-κB activation, as determined by the expression of phosphorylated IκBα (p-IκBα). Experimental Design: The expression profile (mRNA and protein expression) was analyzed with the Centro Nacional de Investigaciones Oncológicas Oncochip, a cDNA microarray containing 6386 cancer-related genes, and a tissue microarray (TMA). The results were correlated with the IgVH mutational states, ZAP-70 expression, cytogenetic alterations, and clinical outcome. Results: We found correlations between the presence of p-IκBα, a surrogate marker of NF-κB 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-κB, as determined by the expression of p-IκBα, 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-IκBα showed longer overall survival than cases with lower expression. A Cox regression model was derived to estimate some parameters of prognostic interest: IgVH mutational status, ZAP-70, and p-IκBα expression. The multivariate analysis disclosed p-IκBα and ZAP-70 expression as independent prognostic factors of survival. Conclusions: A variable degree of activation of NF-κB, as determined by the expression of p-IκBα, is an identifiable event in CLL, and is correlated with changes in the expression profile and overall survival.