Interferon‐alpha up‐regulates bcl‐2 expression and protects B‐CLL cells from apoptosis in vitro and in vivo

Publisher Website
Google Scholar
Abstract
Summary. The bcl‐2 oncoprotein, which is involved in the t(14.18) translocation, protects cells against apoptosis. We examined the effects of interferon‐alpha (IFN‐α) on bcl‐2 protein expression and apoptosis in B‐chronic lymphocytic leukaemia (B‐CLL) cells. None of 12 patients with B‐CLL examined expressed the t(14,18) translocation; however, all these, and seven other patients, expressed significant levels of bcl‐2 protein. In vitro, IFN‐α (500U/ml over 18 h) increased bcl‐2 expression on CLL cells (to 200±23% of control MCF, as determined by indirect immunofluorescence and flow cytometry. n = 10, P < 0.001). All of eight patients who received IFN‐α (3 megaunits subcutaneously three times a week) demonstrated an increase in bcl‐2 expression on circulating malignant cells. CLL cells undergo apoptotic cell death when cultured in vitro (35.6 ± 10.3% DNA fragmentation after 18 h, n = 10). In the presence of IFN‐α, however, DNA fragmentation was reduced to 6.6 ± 5.8% (n = 10, P < 0.001). IFN‐α also protected CLL cells against apoptosis induced by hydrocortisone and gamma irradiation (reducing DNA fragmentation from 63.9 ± 12.6% to 10.8 ± 4.5 % and from 80 ± 2.9% to 5.4 ± 1.6%, respectively, P < 0,001 for both). The protective effect of IFN‐α was dose dependent, and maintained for up to 24 h. Our data demonstrate that bcl‐2 expression and apoptosis of CLL cells can be influenced by cytokines. In addition, it seems unlikely that the observed clinical responses to IFN‐a in patients with CLL are due to a direct effect on the malignant cells.