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Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia

Abstract

Primary B cells from B cell chronic lymphocytic leukaemia (B-CLL) were resistant to the novel selective cytotoxic agent, TNF-related apoptosis-inducing ligand (TRAIL). Low levels of the death-inducing TRAIL receptors, TRAIL-R1 and TRAIL-R2 but not the putative ‘decoy’ receptors, TRAIL-R3 and TRAIL-R4, were expressed on the surface of B-CLL cells. Resistance to TRAIL was upstream of caspase-8 activation, as little or no caspase-8 was processed in TRAIL-treated B-CLL cells. Low levels of a TRAIL death-inducing signalling complex (DISC) were formed in these cells, accompanied by the recruitment of endogenous FADD, caspase-8 and c-FLIPL but not c-FLIPS. Both caspase-8 and c-FLIPL were cleaved to form two stable intermediates of 43 kDa, which remained associated with the DISC. Caspase-8 was not further processed to its active heterotetramer. Thus the resistance of B-CLL cells to TRAIL may be due partly to low surface expression of the death receptors resulting in low levels of DISC formation and also to the high ratio of c-FLIPL to caspase-8 within the DISC, which would prevent further activation of caspase-8. Our results highlight the possibility of sensitising B-CLL cells to TRAIL by modulation of c-FLIP levels or by upregulation of surface expression of death receptors.

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Abbreviations

B-CLL:

B-cell chronic lymphocytic leukaemia

Bis:

bisindolylmaleimide

DISC:

death-inducing signalling complex

FADD:

Fas-associated death domain protein

c-FLIP:

cellular FLICE inhibitory protein

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

TRAIL:

Tumour necrosis factor-related apoptosis-inducing ligand

PS:

phosphatidylserine

TRAIL-R:

TRAIL receptor

XIAP:

X-linked inhibitor of apoptosis protein

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Acknowledgements

We thank Immunex for supplying LZ-TRAIL and the TRAIL receptor antibodies, Dr D Nicholson for c-FLIP antibody and Dr R Waleska for assistance in retrieval of clinical information. This work was supported in part by the Medical Research Council and a grant from the European Union (Grant # QLG1-1999-00739) (to GM Cohen).

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Correspondence to Gerald M Cohen.

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MacFarlane, M., Harper, N., Snowden, R. et al. Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia. Oncogene 21, 6809–6818 (2002). https://doi.org/10.1038/sj.onc.1205853

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