This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Volpe, G. Articles by Saglio, G. Search for Related Content PubMed PubMed Citation Articles by Volpe, G. Articles by Saglio, G.

Alternative BCR/ABL Splice Variants in Philadelphia Chromosome–Positive Leukemias Result in Novel Tumor-Specific Fusion Proteins that May Represent Potential Targets for Immunotherapy Approaches

Departments of ¹ Clinical and Biological Sciences and ² Genetics, Biology and Biochemistry, University of Turin; Laboratories of ³ Tumor Immunology and ⁴ Clinical and Experimental Cytometry, Institute for Cancer Research and Treatment, Candiolo; ⁵ Department of Pathology, San Luigi Hospital, Turin, Italy; ⁶ Laboratory of Hystopathology and ⁷ Interdisciplinary Center for Biomedical Research, Section of Molecular Medicine and Biotechnology, University Campus Bio-Medico; ⁸ National Research Council, Institute of Neurobiology and Molecular Medicine, Laboratory of Gene Medicine, Area of Rome Tor Vergata, Rome, Italy; ⁹ Department of Pharmacology, School of Medicine, University of Milan, Milan, Italy; ¹⁰ U.O. Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; and ¹¹ Bio-Ker, Polaris Scientific Park, Piscinamanna-Pula (Cagliari), Italy

Requests for reprints: Gisella Volpe, Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy. Phone: 39-011-9026609; Fax: 39-011-9038636; E-mail: gisella.volpe{at}unito.it.

Imatinib currently represents the standard treatment in the early chronic phase of chronic myelogenous leukemia (CML), thanks to the high percentage of cytogenetic complete remission achieved, but it is yet unclear to what extent it can eradicate leukemia. Therefore, different vaccination strategies have been suggested, mainly based on the exploitment of the junctional peptides spanning the fusion region of the Bcr/Abl proteins. To identify new potential immunologic targets, 63 Philadelphia chromosome–positive patients and 6 BCR/ABL–positive cell lines were tested in nested reverse transcriptase PCR to detect the presence of BCR/ABL transcripts arising from the alternative splicing of the main BCR/ABL transcripts. We could detect BCR/ABL transcripts with junctions between BCR exon 1, 13, or 14 and ABL exon 4 in 80% of patients and 84% of cell lines, beside the main fusion transcripts. Translation products of these transcripts were characterized at their COOH terminus by a large amino acid portion derived from the out of frame (OOF) reading of ABL gene. These proteins were detected in BCR/ABL–positive cell lines by immunoprecipitation and immunohistochemistry. Finally, we determined whether OOF-specific CD8⁺ T cells could be found in the peripheral blood of CML patients and whether they could acquire effector function following in vitro sensitization with OOF-derived peptides predicted to bind to human leucocyte antigen (HLA)-A2 and HLA-A3 molecules. We detected the presence of OOF-specific CD8⁺ T cells in four of four patients studied, and in one case, these T cells exhibited specific cytotoxic activity against both peptide-pulsed targets and autologous primary CML cells. [Cancer Res 2007;67(11):5300–7]

This article has been cited by other articles:

				N. B. Quigley, D. C. Henley, R. A. Hubbard, J. Laudadio, and R. D. Press ABL Kinase Domain Pseudoexon Insertion Is Not Uncommon in BCR-ABL Transcripts J. Mol. Diagn., September 1, 2008; 10(5): 475 - 476. [Abstract] [Full Text] [PDF]

				J. D. Fackenthal and L. A. Godley Aberrant RNA splicing and its functional consequences in cancer cells Dis. Model. Mech., July 1, 2008; 1(1): 37 - 42. [Abstract] [Full Text] [PDF]

				J. Laudadio, M. W.N. Deininger, M. J. Mauro, B. J. Druker, and R. D. Press An Intron-Derived Insertion/Truncation Mutation in the BCR-ABL Kinase Domain in Chronic Myeloid Leukemia Patients Undergoing Kinase Inhibitor Therapy J. Mol. Diagn., March 1, 2008; 10(2): 177 - 180. [Abstract] [Full Text] [PDF]