Investigating hairy cell leukemia dysregulations. Looking for interferon alpha site of action in hairy cells.

ABSTRACT

One of the most striking characteristics of hairy cell leukemia (HCL) is its remarkable responsiveness to alpha-interferon (IFN-alpha) therapy. IFN-alpha is a multifunctional cytokine able to regulate the growth, differentiation and recirculation of normal and malignant B lymphocytes. These activities have been extensively studied in hairy cells, but none of these properties has been shown to fully account for IFN-alpha responsiveness. Numerous data now support the idea that IFN-alpha exerts its therapeutic effect both indirectly, through stimulation of immunocompetent cells, and directly on the hairy cells. Our approach to investigate the mode action of IFN-alpha in HCL has been to identify abnormalities which occur in these tumor cells and then to ascertain whether these abnormalities can be rectified by IFN-alpha treatment. A high level of free Ca2+ in the cytoplasm of hairy cells was identified. Increases in cytosolic Ca2+ are believed to be a pivotal signal in regulating cell proliferation, cell differentiation and cell death. These high Ca2+ levels in hairy cells could be reduced upon treatment with IFN-alpha either in vitro or in vivo, probably acting by reducing Ca2+ influx into the leukemic cells. Moreover, the effect of IFN-alpha on [Ca2+]i seems to be correlated with alteration in the pattern of kinase/phosphatase activities and with down-regulation of CD20 phosphorylation, a B cell specific phosphoprotein involved in Ca2+ influx across the plasma membrane.