HLA-B8 and HLA-A3 coexpressed with HLA-B8 are associated with a reduced risk of the development of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by the chromosomal transloc ation t(9;22) resulting in the chimeric bcr-abl oncogene that encodes the P 210 fusion protein, which contains a unique amino acid sequence. If peptide s derived from the leukemia-specific part of P210 are expressed in HLA mole cules on the cell membrane of leukemic cells, an immunological response may occur. Recent studies using synthetic peptides identical to the bcr-abl fu sion region showed that some peptides are capable of binding to HLA-AB, -A1 1, and -88 molecules. Cytotoxic T-cel responses have been induced against b cr-abl-derived synthetic peptides bound to HLA-AB and -B8. We hypothesized that if antigen processing of the P210 fusion protein leads to presentation of peptides from the fusion region by major histocompatibility complex (MH C) molecules in vivo, this may be reflected in a diminished incidence of CM L in individuals expressing HLA-A3, -A11, or -88. Consequently, lower frequ encies of these antigens would be expected in patients with CML compared wi th unaffected individuals. A case-control study and a meta-analysis were pe rformed to test this hypothesis. The multicenter case-control study compare d patients with CML from the data base of the European Group for Blood and Marrow Transplantation (EBMT) with unaffected individuals from the registry of bone Marrow Donors Worldwide. Patients and controls were matched per co untry. The meta-analysis consisted of five studies reported in the literatu re. The multicenter case-control study consisting of 1,899 patients and 512 ,363 bone marrow donors as controls yielded odds ratios (ORs) of 0.90 (95% confidence interval [CI], 0.80 to 1.00) for HLA-A3, 1.16 (95% CI, 1.02 to 1 .33) for HLA-A11, and an OR of 0.73 (95% CI, 0.65 to 0.82) for HLA-B8. Coex pression of HLA-A3 and HLA-B8 gave an OR of 0.51 (95% CI, 0.40 to 0.67). Th is can be translated in a protective effect of 27% for HLA-B8, 10% for HLA- AB, and 49% protection for the combination of HLA-AB and HLA-B8. The meta-a nalysis comprising 463 CML patients and 4,912 controls showed a 29% risk re duction for individuals expressing HLA-B8 (OR of 0.71; 95% CI, 0.52 to 0.97 ), but an OR of 1.19 (95% CI, 0.90 to 1.56) for HLA-AB and an OR of 1.09 (9 5% CI, 0.80 to 1.50) for HLA-A11. In conclusion, these results indicate tha t HLA-B8 expression, in particular when HLA-AB is coexpressed, is associate d with a diminished incidence of CML. A biological mechanism may be that pr esentation of bcr-abl breakpoint peptides in these HLA molecules can induce a protective immune response. (C) 1999 by The American Society of Hematolo gy.