2.47 p53 Homolog p63 Promotes Apoptosis and Chemosensitivity in Chronic Lymphocytic Leukemia B-Cells

Abstract

in cell culture medium were measured by enzyme-linked immunosorbent assay (ELISA) and activation of STAT3 and NFB was indicated by the ratio of p-STAT3/STAT3 and p-NFB/NFB. Patients with high levels of p-STAT3/STAT3 and/or p-NFB/ NFB had higher levels of IL-6 production. The level of IL-6 production significantly correlated with STAT3 activation (R 0.856, p 0.001) and NFB activation (R 0.815, p 0.001). Inhibition of constitutive STAT3 and NFB activation by the STAT3 phosphorylation inhibitor, diphenylporphyrin, and the NFB inhibitor, caffeic acid phenethyl ester (CAPE), blocked IL-6 production by 40% on average (p 0.004, p 0.003), active STAT3 or NFB significant increase IL-6 secretion. Analyzing the level of autocrine IL-6 production with in vitro spontaneous apoptosis in CLL cells from 38 patients, we found that patients with higher levels of IL-6 production (more than median) had significantly less apoptosis compared with those below the median (23% vs. 42.2% in average, p 0.0001). Correlation between the levels of autocrine IL-6 production and cell viability in 38 patients (CLL cells were incubated for 48 hours in vitro) was significant (R 0.72, p 0.0001). High IL-6 production was also associated with a shorter average time to first treatment (0.5 vs. 3 years, p 0.0023). This study demonstrates that autocrine IL-6 production correlates with STAT3 and NFB activation and apoptosis resistance in CLL. Furthermore, higher IL-6 production is associated with biological markers of poor prognosis and earlier treatment.