Blockade of death receptor-mediated pathways early in the signaling cascade coincides with distinct apoptosis resistance in cutaneous T-cell lymphoma cells

Control of apoptosis via death ligands plays a basic role for lymphocyte homeostasis and lymphoma development. In this study, cutaneous T- cell lymphoma ( CTCL) cell lines revealed pronounced resistance to death ligands as compared to cell lines of T- cell acute lymphoblastic leukemia ( T- ALL). The proapoptotic activity of tumor necrosis factor ( TNF)-alpha was blocked, sensitivity to TNF- related apoptosis- inducing ligand was significantly reduced, and 1/ 4 CTCL cell lines was resistant to CD95 activation. In parallel, there was no activation of effector caspase- 3 and initiator caspase- 8 in nonresponsive CTCL cells, whereas caspase- 10 was cleaved selectively in sensitive CTCL cells. No indication for a responsibility of typical downstream regulators of apoptosis was obtained, but loss of CD95 was found in 1/ 4, loss of TNF- R1 in 3/ 4, loss of caspase- 10 in 2/ 4, loss of Bid in 1/ 4, and overexpression of cellular flice inhibitory protein was found in 4/ 4 CTCL cell lines. This clearly indicates an inhibition of apoptosis early in the extrinsic cascade, namely at the formation of the death- inducing signaling complex. Parallels with regard to expression of apoptosis regulators were seen in peripheral blood mononuclear cells and biopsies of CTCL patients. This study may indicate defects in apoptosis in CTCL and may help to guide CTCL therapy.