Integrating Prognostic Markers and Cellular Signaling Identifies More Chronic Lymphocytic Leukemia Patients with Adverse Prognosis.

Abstract

In this study we devised an equation that provides a new way of identifying B-cell chronic lymphocytic leukemia (CLL) patients who will require early therapeutic intervention. The equation was developed by studying the biology of the disease with a focus on cell signal transduction. Using statistical analysis, we show that measured tyrosine phosphorylation can be described as a function of VH gene mutation status, and the expression of ZAP-70 and CD38 (r2 = 0.81, n = 49). Furthermore, we show that tyrosine phosphorylation has biological relevance as it sets a threshold for the activation of the transcription factor, NF-kB, resulting in the modulation of cell survival. Using the equation derived from our training dataset we calculated tyrosine phosphorylation in a cohort of 155 unselected CLL patient samples. The patient cohort was then divided into those with calculated tyrosine phosphorylation above or below the threshold required to activate NF-kB. Patients with high calculated tyrosine phosphorylation had a shorter time to first treatment. This method identified more patients at risk of requiring early treatment than VH gene mutation status, ZAP-70 or CD38. Furthermore, calculated tyrosine phosphorylation identifies patients that will require early intervention within the mutated VH gene cohort and even patients that have Stage A disease.