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

Marion MacFarlane; Nicholas Harper; Roger T Snowden; Martin J S Dyer; Georgina A Barnett; J Howard Pringle; Gerald M Cohen

doi:10.1038/sj.onc.1205853

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

Oncogene. 2002 Oct 3;21(44):6809-18. doi: 10.1038/sj.onc.1205853.

Authors

Marion MacFarlane¹, Nicholas Harper, Roger T Snowden, Martin J S Dyer, Georgina A Barnett, J Howard Pringle, Gerald M Cohen

Affiliation

¹ MRC Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.

PMID: 12360407
DOI: 10.1038/sj.onc.1205853

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-FLIP(L) but not c-FLIP(S). Both caspase-8 and c-FLIP(L) were cleaved to form two stable intermediates of approximately 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-FLIP(L) 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing*
Aged
Aged, 80 and over
Apoptosis Regulatory Proteins
Apoptosis*
CASP8 and FADD-Like Apoptosis Regulating Protein
Carrier Proteins / analysis
Caspase 8
Caspase 9
Caspases / analysis
Cycloheximide / pharmacology
Fas-Associated Death Domain Protein
Female
Humans
Intracellular Signaling Peptides and Proteins*
Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
Male
Membrane Glycoproteins / physiology*
Middle Aged
Proteins / analysis
Receptors, TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor
TNF-Related Apoptosis-Inducing Ligand
Tumor Necrosis Factor-alpha / physiology*
X-Linked Inhibitor of Apoptosis Protein

Substances

Adaptor Proteins, Signal Transducing
Apoptosis Regulatory Proteins
CASP8 and FADD-Like Apoptosis Regulating Protein
CFLAR protein, human
Carrier Proteins
FADD protein, human
Fas-Associated Death Domain Protein
Intracellular Signaling Peptides and Proteins
Membrane Glycoproteins
Proteins
Receptors, TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor
TNF-Related Apoptosis-Inducing Ligand
TNFRSF10A protein, human
TNFRSF10B protein, human
TNFSF10 protein, human
Tumor Necrosis Factor-alpha
X-Linked Inhibitor of Apoptosis Protein
XIAP protein, human
Cycloheximide
CASP8 protein, human
CASP9 protein, human
Caspase 8
Caspase 9
Caspases