HLA-DR4 is associated with a diminished risk of the development of chronicmyeloid leukemia (CML)

CML is characterized by the chromosomal translocation t(9;22) (q34;q11) res ulting in the chimeric bcr-abl oncogene that encodes P210 fusion proteins w ith novel amino acid sequences in the breakpoint region. If these peptides derived from P210 are presented by HLA molecules on the cell membrane of le ukemic cells an immunological response may occur. Recent studies using synt hetic peptides identical to the bcr-abl fusion region revealed that some pe ptides are capable of binding to the class I molecules HLA-A2,-A3,-A11 and -B8 and the class II molecules HLA-DR1, -DR2, -DR3, -DR4 and -DR11. Moreove r T cell responses have been induced against bcr-abl-derived synthetic pept ides bound to some of these HLA molecules. For HLA class I, we have previou sly shown that individuals expressing HLA-A3 and -B8 have a diminished risk of development of CML. To assess a similar protective effect of class II m olecules we performed a large multi-center study. This study compared the f requencies of HLA-DR1, -DR2, -DR3, -DR4 and -DR11 of patients with CML from the database of the EBMT (n=1462) with unaffected individuals from the reg istry of Bone Marrow Donors Worldwide (n=500 596). Patients and controls we re matched per country. This analysis yielded significantly lower odds rati os (ORs) of 0.86 (95% C1 0.75-0.98) for HLA-DR3 and of 0.80 (95% CI 0.71-0. 89) for HLA-DR4. The OR was 0.91 (95% CI 0.80-1.04) for HLA-DR1, 1.05 (95% CI 0.94-1.18) for HLA-DR2 and 0.87 (95% CI 0.74-1.01) for HLA-DR11. To asse ss a possible effect of the linkage disequilibrium between HLA-B8 and HLA-D R3 we found that coexpression of HLA-B8 and HLA-DR3 gave an OR of 0.84 (95% CI 0.72-0.98), whereas HLA-DR3 positive/HLA-B8 negative individuals showed an OR of 1.02 (95% CI 0.84-1.24). This means that the protective effect of HLA-DR3 of the development of CML was probably caused by its linkage diseq uilibrium with HLA-B8. In contrast, as there is no linkage disequilibrium o f HLA-DR4 with HLA-A3 or HLA-B8, the results indicate that HLA-DR4 expressi on itself is associated with a diminished incidence of CML possibly by the presentation of bcr-abl breakpoint peptides in these HLA molecules on the m embrane of the leukemic cells.