TRAIL signals to apoptosis in chronic lymphocytic leukaemia cells primarily through TRAIL-R1 whereas cross-linked agonistic TRAIL-R2 antibodies facilitate signalling via TRAIL-R2

Alessandro Natoni, Marion MacFarlane, Satoshi Inoue, Renata Walewska, Aneela Majid, Deborah Knee, David R. Stover, Martin J.S. Dyer, Gerald M. Cohen

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)568-577
Number of pages10
JournalBritish Journal of Haematology
Volume139
Issue number4
DOIs
Publication statusPublished - 2007 Nov
Externally publishedYes

Keywords

  • Apoptosis
  • Chronic lymphocytic leukaemia
  • Cross-linking
  • TRAIL
  • TRAIL-R-antibodies

ASJC Scopus subject areas

  • Hematology

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