TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies

Marion MacFarlane, Susan L. Kohlhaas, Michael J. Sutcliffe, Martin J S Dyer, Gerald M. Cohen

    Research output: Contribution to journalArticlepeer-review


    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its agonistic antibodies, which are currently in early clinical trials for treating various malignancies, induce apoptosis through triggering of either TRAIL-R1 or TRAIL-R2. Based on studies using agonistic monoclonal antibodies, we recently proposed that primary chronic lymphocytic leukemic cells seem to signal apoptosis primarily through TRAIL-R1. We have now synthesized mutant forms of TRAIL specific for TRAIL-R1 or TRAIL-R2. The selectivity of these mutants to induce apoptosis in cell lines is due to selective binding to their cognate receptors resulting in apoptosis via formation of a death-inducing signaling complex. Using these mutants, we now unequivocally show that primary cells from patients with chronic lymphocytic leukemia and mantle cell lymphoma signal to apoptosis almost exclusively through TRAIL-R1. Thus, no significant therapeutic benefit can be anticipated from treating such patients with agents currently in clinical trials that signal predominantly through TRAIL-R2, such as HGS-ETR2 or Apo2L/TRAIL. Our study highlights the necessity to determine whether primary cells from a particular tumor signal via TRAIL-R1 or TRAIL-R2. Such information will provide a rational approach to optimize TRAIL therapy. ©2005 American Association for Cancer Research.
    Original languageEnglish
    Pages (from-to)11265-11270
    Number of pages5
    JournalCancer Research
    Issue number24
    Publication statusPublished - 15 Dec 2005


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