Response of hairy cells to IFN- (cid:1) involves induction of apoptosis through autocrine TNF- (cid:1) and protection by adhesion

Although hairy cell leukemia is uniquely sensitivetointerferon- (cid:1) (IFN- (cid:1) ),thebiologic basisforthisphenomenonremainsunclear. Here we examine the effects of IFN- (cid:1) on cultured hairy cells (HCs), taking into account the possible modifying influence of cell adhesion. We make the novel observa-tionthattherapeuticconcentrationsofIFN- (cid:1) kill nonadherent HCs by inducing apoptosis. In keeping with the persistence of HCs in tissues during therapy, such killing was inhibited by integrin-mediated adhesion to vitronectin or fibronectin. Exposure of HCs to IFN- (cid:1) resulted in a marked increase in tumor necrosis factor- (cid:1) (TNF- (cid:1) ) secretion. Furthermore, blocking antibodies to TNF-RI or TNF-RII protected HCs from IFN- (cid:1) – induced apoptosis, demonstrating that such killing was mediated by TNF- (cid:1) . In the absence of IFN- (cid:1) , exogenous TNF- (cid:1) did not induce HC apoptosis, showing that IFN- (cid:1) sensitized HCs to the proapoptotic effect of autocrine TNF- (cid:1) . This sensitization to TNF- (cid:1) –induced killing was at-tributabletosuppressionofIAP(inhibitors of apoptosis) production known to be regulated by the cytoprotective nuclear factor– (cid:2) B–dependent arm of TNF- (cid:1) signaling. Moreover, engagement of the receptors for fibronectin or vitronectin prevented this IFN- (cid:1) –induced down-regulation of IAPs. Understanding of the signals involved in the combined effects of IFN- (cid:1) and TNF- (cid:1) and abrogation of those induced by integrin engagement offers the possibility of sensitizing other malignant cells to IFN- (cid:1) –induced killing and thereby extending the therapeutic use ofthiscytokine.(Blood.2002;100:647-653)

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