INVESTIGATING HAIRY-CELL LEUKEMIA DYSREGULATIONS - LOOKING FOR INTERFERON A SITE OF ACTION IN HAIRY-CELLS

One of the most striking characteristics of hairy cell leukemia (HCL) is its remarkable responsiveness to alpha-interferon (IFN-alpha) thera py. IFN-alpha is a multifunctional cytokine able to regulate the growt h, differentiation and recirculation of normal and malignant B lymphoc ytes. These activities have been extensively studied in hairy cells, b ut none of these properties has been shown to fully account for IFN-al pha 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 t o 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 identifie d. Increases in cytosolic Ca2+ are believed to be a pivotal signal in regulating cell proliferation, cell differentiation and cell death. Th ese high Ca2+ levels in hairy cells could be reduced upon treatment wi th IFN-alpha either in vitro or in vivo, probably acting by reducing C a2+ influx into the leukemic cells. Moreover, the effect of IFN-alpha on [Ca-2+](i) seems to be correlated with alteration in the pattern of kinase/phosphatase activities and with down-regulation of CD20 phosph orylation, a B cell specific phosphoprotein involved in Ca2+ influx ac ross the plasma membrane.