Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an interferon (IFN)-induced molecule with apoptotic activity. We examined gene mutations in the death domains of TRAIL receptor 1 (TRAIL-R1) and TRAIL receptor 2 (TRAIL-R2), and in the TRAIL gene promoter in 46 chronic myelogenous leukemia (CML) patients. In 23 of the 46 patients, all the coding regions of TRAIL-R2 were also examined. However, no mutation or loss of heterozygosity was found. Furthermore, no mutation in the death domains of TRAIL-R1 and TRAIL-R2 genes, which causes amino acid change, was found in 18 myelodysplastic syndrome (MDS) patients. Ribonuclease protection assay (RPA) and real-time quantitative polymerase chain reaction using polymorphonuclear neutrophils of five new CML patients showed that the TRAIL mRNA expression was very low before in vitro IFN-α stimulation and markedly upregulated after IFN-α stimulation. FAS mRNA was also upregulated with IFN-α stimulation but the fold induction was far lower than that of TRAIL mRNA. In addition, RPA revealed that the ratio of (TRAIL-R1 plus TRAIL-R2) to TRAIL-R3 was also increased after IFN-α stimulation. Taken together, gene mutations of TRAIL-R1, TRAIL-R2 are infrequent in patients with CML and MDS. Andso is the TRAIL promoter for CML. These mutations seem unrelated to tumorigenesis, disease progression, and response to IFN-α therapy in CML. A markedly high induction of TRAIL mRNA by IFN-α may have some relevance to IFN-α action in CML patients.

Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA, Goodwin RG: Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995;3:673–682.
Wajant K, Pfizenmaier K, Scheurich P: TNF-related apoptosis inducing ligand (TRAIL) and its receptors in tumor surveillance and cancer therapy. Apoptosis 2002;7:449–459.
Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A: Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996;271:12687–12690.
Almasan A, Ashkenazi A: Apo2L/TRAIL: Apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev 2003;14:337–348.
MacFarlane M: TRAIL-induced signaling and apoptosis. Toxicol Lett 2003;139:89–97.
Kayagaki N, Yamaguchi N, Nakayama M, Eto H, Okumura K, Yagita H: Type I interferons (IFNs) regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression on human T cells: A novel mechanism for the antitumor effects of type I IFNs. J Exp Med 1999;189:1454–1460.
Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B, Hillan K, Totpal K, DeForge L, Schow P, Hooley J, Sherwood S, Pai R, Leung S, Khan L, Gliniak B, Bussiere J, Smith CA, Strom SS, Kelley S, Fox JA, Thomas D, Ashkenazi A: Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 2001;7:383–385.
Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Barker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A: Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997;277:818–821.
Zang DY, Goodwin RG, Loken MR, Bryant E, Deeg HJ: Expression of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L, and its receptors in myelodysplastic syndrome: Effects on in vitro hemopoiesis. Blood 2001;98:3058–3065.
Oshima K, Yanase N, Ibukiyama C, Yamashina A, Kayagaki N, Yagita H, Muzoguchi J: Involvement of TRAIL/TRAIL-R interaction in IFNα-induced apoptosis of Daudi B lymphoma cells. Cytokine 2001;14:193–201.
Wuchter C, Krappmann D, Cai Z, Ruppert V, Scheidereit C, Dörken B, Ludwig W-D, Karawajew L: In vitro susceptibility to TRAIL-induced apoptosis of acute leukemia cells in the context of TRAIL receptor gene expression and constitutive NF-κB activity. Leukemia 2001;15:921–928.
Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ: Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 1998;161:2833–2840.
Fisher MJ, Virmani AK, Wu L, Aplenc R, Harper JC, Powell SM, Rebbeck TR, Sidransky D, Gazdar AF, El-Deiry WS: Nucleotide substitution in the ectodomain of TRAIL receptor DR4 is associated with lung cancer and head and neck cancer. Clin Cancer Res 2001;7:1688–1697.
Pai SI, Wu GS, Ozoren N, Wu L, Jen J Sidransky D, El-Deiry WS: Rare loss-of function mutation of a death receptor gene in head and neck cancer. Cancer Res 1998;58:3513–3518.
Arai T, Akiyama Y, Okabe S, Saito K, Iwai T, Yuasa Y: Genomic organization and mutation analyses of the DR5/TRAIL receptor 2 gene in colorectal carcinomas. Cancer Lett 1998;133:197–204.
Wu WG, Soria JC, Wang L, Kemp BL, Mao L: TRAIL-R2 is not correlated with p53 status and is rarely mutated in non-small cell lung cancer. Anticancer Res 2000;20:4525–4529.
Lee SH, Shin MS, Kim HS, Lee HK, Park WS, Kim SY, Lee JH, Han SY, Park JY, Oh RR, Jang JJ, Han JY, Lee JY, Yoo NJ: Alterations of the DR5/TRAIL receptor 2 gene in non-small cell lung cancers. Cancer Res 1999;59:5683–5686.
Shin MS, Kim HS, Lee SH, Park WS, Kim SY, Park JY, Lee JH, Lee SK, Lee SN, Jung SS, Han JY, Kim H, Lee JY, Yoo NJ: Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers. Cancer Res 2001;61:4942–4946.
Seitz S, Wassmuth P, Fischer J Nothnagel A, Jandrig B, Schlag PM, Scherneck S: Mutation analysis and mRNA expression of trail-receptors in human breast cancer. Int J Cancer 2002;102:117–128.
Jeng YM, Hsu HC: Mutation of the DR5/TRAIL receptor 2 gene is infrequent in hepatocellular carcinoma. Cancer Lett 2002;181:205–208.
Lee SH, Shin MS, Kim HS, Lee HK, Park WS, Kim SY, Lee JH, Han SY, Park JY, Oh RR, Kang CS, Kim KM, Jang JJ, Nam SW, Lee JY, Yoo NJ: Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin’s lymphoma. Oncogene 2001;20:399–403.
Chawla-Sarkar M, Lindner DJ, Liu Y-F, Williams BR, Sen GC, Silerman RH, Borden EC: Apoptosis and interferons: Role of interferon-stimulated genes as mediators of apoptosis. Apoptosis 2003;8:237–249.
Gong B, Almasan A: Genomic organization and transcriptional regulation of human Apo2/TRAIL gene. Biochem Biophys Res Commun 2000;278:747–752.
Talpaz M, Kantarjian HM, McCredie K, Trujillo JM, Keating MJ, Gutterman JU: Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia. N Engl J Med 1986;314:1065–1069.
Takahashi N, Miura I, Saitoh K, Miura AB: Lineage involvement of stem cells bearing the Philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. Blood 1998;92:4758–4763.
Sambrook J, Fritsch EF, Maniatis T: Molecular Cloning: A Laboratory Manual, ed 2. New York, Cold Spring Harbor Laboratory Press, 1989.
Oto M, Miyake Y, Yuasa Y: Optimization of nonradioisotopic single strand conformation polymorphism analysis with a conventional minislab gel electrophoresis apparatus. Anal Biochem 1993;213:19–22.
Tanaka H, Samuel CE: Mechanism of interferon action: Structure of the mouse PKR gene encoding the interferon-inducible RNA-dependent protein kinase. Proc Natl Acad Sci USA 1994;91:7995–7999.
Tanaka H, Samuel CE: Mouse interferon-inducible RNA-dependent protein kinase Pkr gene: Cloning and sequence of the 5′-flanking region and functional identification of the minimal inducible promoter. Gene 2000;246:373–382.
Johansson B, Fioretos T, Mitelman F: Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002;107:76–94.
Tanaka H, Tanaka K, Oguma N, Ito K, Ito T, Kyo T, Dohy H, Kimura A: Effect of interferon alpha on chromosome abnormalities in treated chronic myelocytic leukemia patients. Cancer Genet Cytogenet, in press.
Selleri C, Sato T, Del Vecchio L, Luciano L, Barrett AJ, Rotoli B, Young NS, Maciejewski JP: Involvement of Fas-mediated apoptosis in the inhibitory effects of interferon-α in chronic myelogenous leukemia. Blood 1997;89:957–964.
Selleri C, Maciejewski JP, Pane F, Luciano L, Raiola AM, Mostarda I, Salvatore F, Rotoli B: Fas-mediated modulation of Bcr/Abl in chronic myelogenous leukemia results in differential effects on apoptosis. Blood 1998;92:981–989.
Tecchio C, Huber V, Scapini P, Calzetti F, Margotto D, Todeschini G, Pilla L, Martinelli G, Pizzolo G, Rivoltini L, Cassatella MA: IFNα-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity on leukemic cells. Blood 2004;103:3837–3844.
Leaman DW, Chawla-Sarker M, Vyas K, Reheman M, Tamai K, Toji S, Borden EC: Identification of X-linked inhibitor of apoptosis-associated factor-1 as an interferon-stimulated gene that augments TRAIL Apo2L-induced apoptosis. J Biol Chem 2002;277:28504–28511.
Kumar-Sinha C, Varambally S, Sreekumar A, Chinnaiyan AM: Molecular cross-talk between the TRAIL and interferon signaling pathway. J Biol Chem 2002;277:575–585.
Stanger BZ, Leder P, Lee TH, Kim E, Seed B: RIP: A novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and caused cell death. Cell 1995;81:513–523.
Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P: The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 1998;8:297–303.
Cusson N, Oikemus S, Kilpatrick ED, Cunningham L, Kelliher M: The death domain kinase RIP protects thymocytes from tumor necrosis factor receptor type 2-induced cell death. J Exp Med 2002;196:15–26.
Chawla-Sarkar M, Leaman DW, Jacobs BS, Borden EC: IFN-β pretreatment sensitizes human melanoma cells to TRAIL/Apo2 ligand-induced apoptosis. J Immunol 2002;169:847–855.
Kim KB, Choi YH, Kim IK, Chung CW, Kim BJ, Park YM, Jung YK: Potentiation of Fas- and TRAIL-mediated apoptosis by IFN-γ in A549 lung epithelial cells: Enhancement of caspase-8 expression through IFN-response element. Cytokine 2002;20:283–288.
Shigeno M, Nakao K, Ichikawa T, Suzuki K, Kawakami A, Abiru S, Miyazoe S, Nakagawa Y, Ishikawa H, Hamasaki K, Nakata K, Ishii N, Eguchi K: Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation. Oncogene 2003;22:1653–1662.
Toomey NL, Deyev VV, Wood C, Boise LH, Scott D, Liu LH, Cabral L, Podack ER, Barber GN, Harrington WJ Jr: Induction of a TRAIL mediated suicide program by interferon alpha in primary effusion lymphoma. Oncogene 2001;20:7029–7040.
Mitsiades CS, Treon SP, Mitsiades N, Shima Y, Richardson P, Schlossman R, Hideshima T, Anderson KC: TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: Therapeutic applications. Blood 2001;98:795–804.
Mitsiades N, Mitsiades CS, Poulaki V, Anderson KC, Treon SP: Intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human multiple myeloma cells. Blood 2002;99:2162–2171.
Uno K, Inukai T, Kayagaki N, Goi K, Sato H, Nemoto A, Takahashi K, Kagami K, Yamaguchi N, Yagita H, Okumura K, Koyama-Okazaki T, Suzuki T, Sugita K, Nakazawa S: TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells. Blood 2003;101:3658–3667.
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