Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 139, Issue 4, Pages 568-577Publisher
WILEY
DOI: 10.1111/j.1365-2141.2007.06852.x
Keywords
TRAIL; apoptosis; chronic lymphocytic leukaemia; cross-linking; TRAIL-R-antibodies
Categories
Funding
- Medical Research Council [MC_U132670597, MC_U132615750, MC_U132685863] Funding Source: Medline
- Medical Research Council [MC_U132615750, MC_U132670597, MC_U132685863] Funding Source: researchfish
- MRC [MC_U132685863, MC_U132670597, MC_U132615750] Funding Source: UKRI
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Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, which is being developed as an anti-tumour agent due to its selective toxicity to tumour cells, induces apoptosis by binding to two membrane-bound receptors, TRAIL-R1 and TRAIL-R2. Clinical trials have been initiated with various preparations of TRAIL as well as agonistic monoclonal antibodies to TRAIL-R1 and TRAIL-R2. Previously we reported that prior treatment of primary chronic lymphocytic leukaemia (CLL) cells with histone deacetylase inhibitors was required to sensitize CLL cells to TRAIL and, using various receptor-selective TRAIL mutant ligands, we demonstrated that CLL cells signalled to apoptosis primarily through TRAIL-R1. Some, but not all, agonistic TRAIL-receptor antibodies require cross-linking in order to induce apoptosis. The present study demonstrated that CLL cells can signal to apoptosis through the TRAIL-R2 receptor, but only after cross-linking of the agonistic TRAIL-R2 antibodies, LBY135 and lexatumumab (HGS-ETR2). In contrast, signalling through TRAIL-R1 by receptor-selective ligands or certain agonistic antibodies, such as mapatumumab (HGS-ETR1), occurs in the absence of cross-linking. These results further highlight important differences in apoptotic signalling triggered through TRAIL-R1 and TRAIL-R2 in primary tumour cells. Such information is clearly important for the rational optimisation of TRAIL therapy in primary lymphoid malignancies, such as CLL.
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