BCR/ABL Leukemia Oncogene Fusion Peptides Selectively Bind to Certain HLA-DR Alleles and Can Be Recognized by T Cells Found at Low Frequency in the Repertoire of Normal Donors

• Published in: Blood 1996-09, Vol.88 (6), p.2118-2124
• Main Authors: Pawelec, Graham, Max, Heiner, Haider, Thomas, Bruserud, Øystein, Merl, Andrea, Silva, Paul da, Kalbacher, Hubert
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Fusion Proteins, bcr-abl - immunology; HLA-DR Antigens - immunology; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - immunology; Lymphocyte Activation; Molecular Sequence Data; Peptides - immunology; T-Lymphocytes - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V88.6.2118.bloodjournal8862118

Chronic myelogenous leukemia (CML) is characterized by the t(9;22) translocation that results in chimeric genes encoding bcr/abl fusion proteins. Junction-spanning sequences represent unique tumor-specific moieties that might be exploited therapeutically. We investigate here the binding of synthetic bcr/abl peptides to various HLA-DR alleles and their recognition by T cells from normal donors and CML patients. A 23-mer b3/a2 peptide bound very strongly to isolated HLA-DRB1*1101 (Dw5) and relatively strongly to DRB1*0301 (Dw3) and DRB1*0402 (Dw10) molecules, as estimated using a competition assay. It failed to bind to several other DR alleles, including three different DR4 alleles. In contrast, a 23-mer b2/a2 peptide bound only to the DRB1*0301 (Dw3) allele. Peripheral blood mononuclear cells from normal donors were sensitized in vitro against the b3/a2 peptide. After four repetitive stimulations, T cells responding to the peptide were found at low frequency in 5 of the 11 donors tested. Three of the five were HLA-DR11+, and all three of the DR11+ donors tested were found to respond. T cells recognizing bcr/abl peptides were not identified in any of the CML patients studied, regardless of HLA type. Finally, even peptide-reactive T-cell lines from normal donors were not stimulated by native CML cells in the absence of exogenous peptide. These results show the presence of low-frequency major histocompatability complex class ll-restricted bcr/abl-responses in the normal T-cell repertoire of donors with certain HLA types, but suggest that unmodified tumor cells cannot be recognized by such peptide-sensitized T cells.