BCR-ABL fusion regions as a source of multiple leukemia-specific CD8+ T-cell epitopes
| Autor: | Marcel Camps, C. J. M. Melief, Ferry Ossendorp, R. Offringa, O C Leeksma, A. de Ru, Jan W. Drijfhout, Jan H. Kessler, Sandra A. Bres-Vloemans, P.A. van Veelen, Arnout Mulder, I J G Huijbers |
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| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
medicine.medical_treatment Molecular Sequence Data Fusion Proteins bcr-abl Epitopes T-Lymphocyte Human leukocyte antigen HLA-C Antigens Biology CD8-Positive T-Lymphocytes Philadelphia chromosome Cancer Vaccines Epitope hemic and lymphatic diseases Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive HLA-A2 Antigen medicine Cytotoxic T cell Humans Amino Acid Sequence HLA-A Antigens Antigen processing Hematology Immunotherapy medicine.disease Fusion protein Virology Peptide Fragments CTL Oncology HLA-B Antigens HLA-B51 Antigen Epitope Mapping Protein Binding |
| Zdroj: | Leukemia. 20(10) |
| ISSN: | 0887-6924 |
| Popis: | For immunotherapy of residual disease in patients with Philadelphia-positive leukemias, the BCR-ABL fusion regions are attractive disease-specific T-cell targets. We analyzed these regions for the prevalence of cytotoxic T lymphocyte (CTL) epitopes by an advanced reverse immunology procedure. Seventeen novel BCR-ABL fusion peptides were identified to bind efficiently to the human lymphocyte antigen (HLA)-A68, HLA-B51, HLA-B61 or HLA-Cw4 HLA class I molecules. Comprehensive enzymatic digestion analysis showed that 10 out of the 28 HLA class I binding fusion peptides were efficiently excised after their C-terminus by the proteasome, which is an essential requirement for efficient cell surface expression. Therefore, these peptides are prime vaccine candidates. The other peptides either completely lacked C-terminal liberation or were only inefficiently excised by the proteasome, rendering them inappropriate or less suitable for inclusion in a vaccine. CTL raised against the properly processed HLA-B61 epitope AEALQRPVA from the BCR-ABL e1a2 fusion region, expressed in acute lymphoblastic leukemia (ALL), specifically recognized ALL tumor cells, proving cell surface presentation of this epitope, its applicability for immunotherapy and underlining the accuracy of our epitope identification strategy. Our study provides a reliable basis for the selection of optimal peptides to be included in immunotherapeutic BCR-ABL vaccines against leukemia. |
| Databáze: | OpenAIRE |
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