Increased non-canonical splicing of autoantigen transcripts provides the structural basis for expression of untolerized epitopes

et al. 2007

Clinical Immunology

We attempted to determine whether the immune reactions elicited by aberrantly expressed testis antigens contribute to the beneficial responses to interferon (IFN)-α therapy and other therapies in patients with polycythemia vera (PV). We screened a human testis cDNA library using SEREX (serological analysis of tumor antigens by screening an expression cDNA library with sera from three patients with PV who had undergone IFN-α-induced or other therapeutics-induced remission). We identified two novel PV associated tumor antigens, PV65 (eIF-2α) and PV13 (protamine 2). These 2 antigens elicited IgG antibody reactions in a subset of PV patients but not in healthy donors, suggesting that they are authentic tumor antigens. Increased phosphorylation of PV65 in response to stimulation of IFN-α, and upregulation of PV13 in tumor cells might enhance their abilities in elicitation of immune reactions in patients. These findings provide new insights into the mechanism underlying the regulation of the self-antigen repertoire in eliciting anti-tumor immune reactions in patients with polycythemia vera, and suggest their potential as the targets of novel immunotherapy.

Section: Bioinformatic Analysesmentioning

confidence: 99%

Section: Bioinformatic Analysesmentioning

confidence: 99%

Novel tumor antigens elicit anti-tumor humoral immune reactions in a subset of patients with polycythemia vera

et al. 2007

Clinical Immunology

“…Sequence analyses were performed using the National Center for Biotechnology Information (NCBI)-GenBank databases (͗www.ncbi.nlm.nih.gov/ ͘), NCBI-conserved domain databases, and the PROSITE analysis (͗http:// us.expasy.org/cgi-bin/scanprosite͘) to determine whether cloned sequences were related or identical with genes, proteins, or protein domains in the databases (20). The gene organizations, such as intron-exon structure and chromosome location, were analyzed by searching in the NCBI-AceView website (20).…”

Section: Bioinformatic Analysesmentioning

confidence: 99%

“…The gene organizations, such as intron-exon structure and chromosome location, were analyzed by searching in the NCBI-AceView website (20). The expression of studied genes was determined by the Northern blots.…”

Section: Bioinformatic Analysesmentioning

confidence: 99%

“…In addition, we proposed a "stimulation-responsive splicing" model in which dominant noncanonical alternative splicing provides a structural basis for generation of untolerized self-Ag epitopes (20,21). Furthermore, we identified an unconventional Ag MPD5 encoded in the antisense strand of the intron 1 of NEK6 gene (Z. Xiong, E. Liu, Y. Yan, R. T. Silver, S. Zhang, Y. Yang, S. Verstovsek, F. Yang, I. H. Chen, F. J. Segura, et al, submitted for publication).…”

mentioning

confidence: 99%

See 1 more Smart Citation

An Unconventional Antigen Translated by a Novel Internal Ribosome Entry Site Elicits Antitumor Humoral Immune Reactions

The Journal of Immunology

et al. 2006

Self-tumor Ags that elicit antitumor immune responses in responses to IFN-α stimulation remain poorly defined. We screened a human testis cDNA library with sera from three polycythemia vera patients who responded to IFN-α 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-α 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-α 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-α stimulation. The eliciting antitumor immune response against unconventional Ag MPD6 in patients with myeloproliferative diseases suggests MPD6 as a potential target of novel immunotherapy.

A Novel Unconventional Antigen MPD5 Elicits Anti-Tumor Humoral Immune Responses in a Subset of Patients with Polycythemia Vera

Int J Immunopathol Pharmacol

et al. 2007

Self Cite

In an effort to define the antigenic mechanism that contributes to beneficial therapeutic outcome in patients with polycythemia vera (PV), we screened a human testis cDNA library with serological cloning derived from sera of three PV patients who had undergone therapeutic-induced remission. As a result, we identified a novel antigen, MPD5, which belongs to the group of cryptic antigens with unconventional genomic intron/exon structure. Moreover, MPD5 elicited IgG antibody responses in a subset of PV patients who had benefited from a variety of therapies--including IFN-alpha, Hydroxyurea, Imatinib mesylate, Anagrelide, and phlebotomy--but not in untreated PV patients or healthy donors, suggesting that MPD5 is a PV-associated, therapy-related antigen. In the granulocytes of PV patients who are responsive to therapy, upregulated MPD5 expression may serve to enhance immune responses. These findings provide new insight into the mechanism underlying regulation of the self-antigen repertoire that elicits anti-tumor immune responses in patients with myeloproliferative diseases, indicating the potential of these self-antigens as targets of novel immunotherapy.