TRAIL-induced eradication of primary tumour cells from multiple myeloma patient bone marrows is not related to TRAIL receptor expression or prior chemotherapy

TNF-related apoptosis-inducing ligand (TRAIL) shares significant homology w ith CD95 (Fas) ligand and has the ability to induce apoptosis in sensitive cells through a caspase-mediated pathway. We have evaluated the activity of purified human recombinant soluble TRAIL (S-TRAIL, comprising residues 114 -281; Blomol, Plymouth Meeting, PA, USA) and a leucine zipper construct of TRAIL (LZ-TRAIL; Immunex, Seattle WA, USA) against myeloma cell lines NCI H 929, U266, RPMI 8226, the FasL-sensitive Jurkat T cell ALL line, the lympho blastoid cell line MC/CAR and primary tumour cells from 16 myeloma patients . Furthermore, we examined the relationship between TRAIL-induced apoptosis and TRAIL receptor expression utilising RT-PCR and flow cytometry. Two of three myeloma cell lines and Jurkat were TRAIL sensitive whereas MC/CAR was relatively resistant. Five of 16 (31%) primary tumours demonstrated greate r than or equal to 20% reduction in myeloma cells following TRAIL incubatio n (20-59%). This did not correlate with prior therapy. Four cell lines (two sensitive) and five primary tumours (two sensitive) demonstrated mRNA expr ession of the intra-cellular death domain containing TRAIL-R1. Variable exp ression of the two decoy (TRAIL-R3 and R4) and soluble (osteoprotegerin) re ceptors was seen and this did not correlate with TRAIL resistance. We concl ude that myeloma cell expression of death effector receptors for TRAIL is i nsufficient to confer sensitivity to TRAIL-induced apoptosis but that in a significant minority of patients, irrespective of prior therapy, tumour cel ls are sensitive to TRAIL. The further investigation of TRAIL as an adjunct to presently available therapies for myeloma is justified.