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* Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140;
Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112;
Department of Medicine, New York Presbyterian-Weill Cornell Medical Center, New York, NY 10021; and
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, and
¶ Department of Medicine, Baylor College of Medicine, Houston, TX 77030
Self-tumor Ags that elicit antitumor immune responses in responses to IFN-
stimulation remain poorly defined. We screened a human testis cDNA library with sera from three polycythemia vera patients who responded to IFN- and identified a novel Ag, MPD6. MPD6 belongs to the group of cryptic Ags without conventional genomic structure and is encoded by a cryptic open reading frame located in the 3'-untranslated region of myotrophin mRNA. MPD6 elicits IgG Ab responses in a subset of polycythemia vera patients, as well as patients with chronic myelogenous leukemia and prostate cancer, suggesting that it is broadly immunogenic. The expression of myotrophin-MPD6 transcripts was up-regulated in some tumor cells, but only slightly increased in K562 cells in response to IFN- treatment. By using bicistronic reporter constructs, we showed that the translation of MPD6 was mediated by a novel internal ribosome entry site (IRES) upstream of the MPD6 reading frame. Furthermore, the MPD6-IRES-mediated translation, but not myotrophin-MPD6 transcription, was significantly up-regulated in response to IFN- stimulation. These findings demonstrate that a novel IRES-mediated mechanism may be responsible for the translation of unconventional self-Ag MPD6 in responsive to IFN- stimulation. The eliciting antitumor immune response against unconventional Ag MPD6 in patients with myeloproliferative diseases suggests MPD6 as a potential target of novel immunotherapy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was partially supported by National Institutes of Health Grant AI054514 (to X.-F.Y.), and Leukemia and Lymphoma Society and the Myeloproliferative Disorders Foundation (to X.-F.Y.), and funds from the Cancer Research and Treatment Fund (to R.T.S.).
2 Address correspondence and reprint requests to Dr. Xiao-Feng Yang, Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140. E-mail address: xfyang{at}temple.edu
3 Abbreviations used in this paper: PV, polycythemia vera; CML, chronic myeloid leukemia; MPD, myeloproliferative disease; ORF, open reading frame; UTR, untranslated region; IRES, internal ribosome entry site; EMCV, encephalomyocarditis virus; EGFP, enhanced GFP.
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  J.-J. Kiladjian, B. Cassinat, S. Chevret, P. Turlure, N. Cambier, M. Roussel, S. Bellucci, B. Grandchamp, C. Chomienne, and P. Fenaux Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera Blood, October 15, 2008; 112(8): 3065 - 3072. [Abstract] [Full Text] [PDF]
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