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Variability in the Degree of Expression of Phosphorylated IB in Chronic Lymphocytic Leukemia Cases With Nodal Involvement

¹ Molecular Pathology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain; ² Department of Genetics and Pathology, Hospital Virgen de la Salud, Toledo, Spain; ³ Department of Pathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; ⁴ Department of Hematology, Hospital Nuestra Señora del Prado, Talavera de la Reina, Toledo, Spain; ⁵ Department of Pathology, Hospital Verge de la Cinta, Tortosa, Spain; and ⁶ Department of Pathology, Hospital Central de Asturias, Oviedo, Spain

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)-B activation, as determined by the expression of phosphorylated IB (p-IB).

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 IgV_H mutational status, ZAP-70 expression, cytogenetic alterations, and clinical outcome.

Results: We found correlations between the presence of p-IB, a surrogate marker of NF-B 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-B, as determined by the expression of p-IB, 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-IB 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-IB expression. The multivariate analysis disclosed p-IB and ZAP-70 expression as independent prognostic factors of survival.

Conclusions: A variable degree of activation of NF-B, as determined by the expression of p-IB, is an identifiable event in CLL, and is correlated with changes in the expression profile and overall survival.

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