TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells.

Abstract	Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) have been implicated in antitumor immunity and therapy. In the present study, we investigated the sensitivity of Philadelphia chromosome (Ph1)-positive leukemia cell lines to TRAIL- or FasL-induced cell death to explore the possible contribution of these molecules to immunotherapy against Ph1-positive leukemias. TRAIL, but not FasL, effectively induced apoptotic cell death in most of 5 chronic myelogenous leukemia-derived and 7 acute leukemia-derived Ph1-positive cell lines. The sensitivity to TRAIL was correlated with cell-surface expression of death-inducing receptors DR4 and/or DR5. The TRAIL-induced cell death was caspase-dependent and enhanced by nuclear factor kappa B inhibitors. Moreover, primary leukemia cells from Ph1-positive acute lymphoblastic leukemia patients were also sensitive to TRAIL, but not to FasL, depending on DR4/DR5 expression. Fas-associated death domain protein (FADD) and caspase-8, components of death-inducing signaling complex (DISC), as well as FLIP (FLICE [Fas-associating protein with death domain-like interleukin-1-converting enzyme]/caspase-8 inhibitory protein), a negative regulator of caspase-8, were expressed ubiquitously in Ph1-positive leukemia cell lines irrespective of their differential sensitivities to TRAIL and FasL. Notably, TRAIL could induce cell death in the Ph1-positive leukemia cell lines that were refractory to a BCR-ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571; Novartis Pharma, Basel, Switzerland). These results suggested the potential utility of recombinant TRAIL as a novel therapeutic agent and the possible contribution of endogenously expressed TRAIL to immunotherapy against Ph1-positive leukemias.
Authors	Kanako Uno, Takeshi Inukai, Nobuhiko Kayagaki, Kumiko Goi, Hiroki Sato, Atsushi Nemoto, Kazuya Takahashi, Keiko Kagami, Noriko Yamaguchi, Hideo Yagita, Ko Okumura, Toshiko Koyama-Okazaki, Toshio Suzuki, Kanji Sugita, Shinpei Nakazawa
Journal	Blood (Blood) Vol. 101 Issue 9 Pg. 3658-67 (May 01 2003) ISSN: 0006-4971 [Print] United States
PMID	12506034 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Amino Acid Chloromethyl Ketones Apoptosis Regulatory Proteins Arabidopsis Proteins Benzamides CASP8 and FADD-Like Apoptosis Regulating Protein CFLAR protein, human Carrier Proteins Death Domain Receptor Signaling Adaptor Proteins Enzyme Inhibitors FASLG protein, human Fas Ligand Protein Intracellular Signaling Peptides and Proteins Leupeptins Membrane Glycoproteins NF-kappa B Neoplasm Proteins Peptides Piperazines Pyrimidines Receptors, TNF-Related Apoptosis-Inducing Ligand Receptors, Tumor Necrosis Factor Recombinant Proteins SN50 peptide TNF-Related Apoptosis-Inducing Ligand TNFRSF10A protein, human TNFRSF10B protein, human TNFSF10 protein, human Tumor Necrosis Factor-alpha benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone acetylleucyl-leucyl-norleucinal Imatinib Mesylate Fatty Acid Desaturases Fad7 protein, Arabidopsis Fusion Proteins, bcr-abl Caspase 1
Topics	Amino Acid Chloromethyl Ketones (pharmacology) Apoptosis (drug effects) Apoptosis Regulatory Proteins Arabidopsis Proteins Benzamides CASP8 and FADD-Like Apoptosis Regulating Protein Carrier Proteins (physiology) Caspase 1 (physiology) Death Domain Receptor Signaling Adaptor Proteins Drug Resistance, Neoplasm Drug Screening Assays, Antitumor Enzyme Inhibitors (pharmacology) Fas Ligand Protein Fatty Acid Desaturases (physiology) Fusion Proteins, bcr-abl (antagonists & inhibitors) Humans Imatinib Mesylate Intracellular Signaling Peptides and Proteins Leukemia, Myelogenous, Chronic, BCR-ABL Positive (pathology) Leupeptins (pharmacology) Membrane Glycoproteins (pharmacology, physiology) NF-kappa B (antagonists & inhibitors) Neoplasm Proteins (antagonists & inhibitors, physiology) Neoplastic Stem Cells (drug effects, pathology) Peptides (pharmacology) Piperazines (pharmacology) Precursor Cell Lymphoblastic Leukemia-Lymphoma (pathology) Pyrimidines (pharmacology) Receptors, TNF-Related Apoptosis-Inducing Ligand Receptors, Tumor Necrosis Factor (physiology) Recombinant Proteins (pharmacology) TNF-Related Apoptosis-Inducing Ligand Tumor Cells, Cultured (drug effects, pathology) Tumor Necrosis Factor-alpha (pharmacology, physiology)

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