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

Br J Haematol. 2007 Nov;139(4):568-77. doi: 10.1111/j.1365-2141.2007.06852.x. Epub 2007 Oct 8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Murine-Derived / pharmacology
  • Antibodies, Monoclonal, Murine-Derived / therapeutic use
  • Apoptosis / drug effects*
  • Cell Communication / drug effects
  • Cell Line, Tumor
  • Cross-Linking Reagents
  • Drug Interactions
  • Ephrins / physiology*
  • Female
  • Humans
  • Hydroxamic Acids / pharmacology
  • Indoles
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Male
  • Middle Aged
  • Panobinostat
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / agonists*
  • TNF-Related Apoptosis-Inducing Ligand / physiology*


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Cross-Linking Reagents
  • Ephrins
  • Hydroxamic Acids
  • Indoles
  • LBY135 monoclonal antibody
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • Panobinostat
  • lexatumumab