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

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 24; pp. 11265 - 11270
• Main Authors: MACFARLANE, Marion, KOHLHAAS, Susan L, SUTCLIFFE, Michael J, DYER, Martin J. S, COHEN, Gerald M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.12.2005
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Biological and medical sciences; Caspase 8; Caspases - metabolism; Fas-Associated Death Domain Protein; Hematologic and hematopoietic diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Mantle-Cell - metabolism; Medical sciences; Membrane Glycoproteins - metabolism; Molecular Sequence Data; Mutation - genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Sequence Homology, Amino Acid; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - metabolism; Signal transduction; Cell death; Lymphoproliferative syndrome; Primary; TNF related apoptosis inducing ligand; Hemopathy; Mutation; Apoptosis; Biological receptor
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-2801

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.