Gene Expression Signatures Separate B-Cell Chronic Lymphocytic Leukemia Prognostic Subgroups Defined by ZAP-70 and CD38 Expression Status.

B-cell chronic lymphocytic leukemia (B-CLL) is a heterogenous disease with a highly variable clinical course and analysis of ZAP-70 and CD38 expression on B-CLL cells allowed for identification of patients with good (ZAP-70⁻CD38⁻) and poor (ZAP-70⁺CD38⁺) prognosis. DNA microarray technology was employed to compare eight ZAP-70⁺CD38⁺ with eight ZAP-70⁻CD38⁻ B-CLL cases. The expression of 358 genes differed significantly between the two subgroups including genes involved in B cell receptor signaling, angiogenesis and lymphomagenesis. Three of these genes, i.e. IRTA4/FcRH2, angiopoietin 2 and Pim2 were selected for further validating studies in a cohort of 94 B-CLL patients. IRTA4/FcRH2 expression as detected by flow cytometry was significantly lower in the poor prognosis subgroup as compared to ZAP-70⁻CD38⁻ B-CLL cells. In healthy individuals IRTA4/FcRH2 protein expression was associated with a CD19⁺CD27⁺ memory cell phenotype. Angiopoietin 2 plasma concentrations were two-fold higher in the poor prognosis subgroup (p<0.05). Pim2 was significantly overexpressed in poor prognosis cases and Binet stage C. Disease progression may be related to proangiogenic processes and strong Pim2 expression.