BCR ABL LEUKEMIA ONCOGENE FUSION PEPTIDES SELECTIVELY BIND TO CERTAINHLA-DR ALLELES AND CAN BE RECOGNIZED BY T-CELLS FOUND AT LOW-FREQUENCY IN THE REPERTOIRE OF NORMAL DONORS/

Chronic myelogenous leukemia (CML) is characterized by the t(9;22) tra nslocation that results in chimeric genes encoding bcr/abl fusion prot eins. Junction-spanning sequences represent unique tumor-specific moie ties that might be exploited therapeutically. We investigate here the binding of synthetic bcr/abl peptides to various HLA-DR alleles and th eir recognition by T cells from normal donors and CML patients, A 23-m er b3/a2 peptide bound very strongly to isolated HLA-DRB11101 (Dw5) a nd relatively strongly to DRB10301 (Dw3) and DRB1*0402 (Dw10) molecul es, as estimated using a competition assay. It failed to bind to sever al other DR alleles, including three different DR4 alleles. In contras t, a 23-mer b2/a2 peptide bound only to the DRB10301 (Dw3) allele. Pe ripheral 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 thre e of the DR11(+) donors tested were found to respond. T cells recogniz ing bcr/abl peptides were not identified in any of the CML patients st udied, regardless of HLA type. Finally, even peptide-reactive T-cell l ines 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 II-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. (C) 1996 by The American Society of Hematology.