Posthuma E F, Falkenburg J H, Apperley J F, Gratwohl A, Roosnek E, Hertenstein B, Schipper R F, Schreuder G M, D'Amaro J, Oudshoorn M, van Biezen J H, Hermans J, Willemze R, Niederwieser D
Departments of Hematology, Immunohematology, and Medical Statistics, Leiden University Medical Center and Europdonor Foundation, Leiden, The Netherlands.
Blood. 1999 Jun 1;93(11):3863-5.
Chronic myeloid leukemia (CML) is characterized by the chromosomal translocation t(9;22) resulting in the chimeric bcr-abl oncogene that encodes the P210 fusion protein, which contains a unique amino acid sequence. If peptides derived from the leukemia-specific part of P210 are expressed in HLA molecules on the cell membrane of leukemic cells, an immunological response may occur. Recent studies using synthetic peptides identical to the bcr-abl fusion region showed that some peptides are capable of binding to HLA-A3, -A11, and -B8 molecules. Cytotoxic T-cell responses have been induced against bcr-abl-derived synthetic peptides bound to HLA-A3 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 (MHC) molecules in vivo, this may be reflected in a diminished incidence of CML in individuals expressing HLA-A3, -A11, or -B8. Consequently, lower frequencies of these antigens would be expected in patients with CML compared with unaffected individuals. A case-control study and a meta-analysis were performed to test this hypothesis. The multicenter case-control study compared 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 country. The meta-analysis consisted of five studies reported in the literature. 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. Coexpression of HLA-A3 and HLA-B8 gave an OR of 0.51 (95% CI, 0.40 to 0.67). This can be translated in a protective effect of 27% for HLA-B8, 10% for HLA-A3, and 49% protection for the combination of HLA-A3 and HLA-B8. The meta-analysis comprising 463 CML patients and 4,912 controls showed a 29% risk reduction 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-A3 and an OR of 1. 09 (95% CI, 0.80 to 1.50) for HLA-A11. In conclusion, these results indicate that HLA-B8 expression, in particular when HLA-A3 is coexpressed, is associated with a diminished incidence of CML. A biological mechanism may be that presentation of bcr-abl breakpoint peptides in these HLA molecules can induce a protective immune response.
慢性髓性白血病（CML）的特征是染色体易位t(9;22)，导致嵌合的bcr-abl癌基因，该基因编码P210融合蛋白，其包含独特的氨基酸序列。如果源自P210白血病特异性部分的肽在白血病细胞膜上的HLA分子中表达，则可能会发生免疫反应。最近使用与bcr-abl融合区域相同的合成肽进行的研究表明，一些肽能够与HLA-A3、-A11和-B8分子结合。已经诱导出针对与HLA-A3和-B8结合的bcr-abl衍生合成肽的细胞毒性T细胞反应。我们推测，如果P210融合蛋白的抗原加工导致主要组织相容性复合体（MHC）分子在体内呈递融合区域的肽，这可能反映在表达HLA-A3、-A11或-B8的个体中CML发病率降低。因此，与未受影响的个体相比，预计CML患者中这些抗原的频率较低。进行了一项病例对照研究和一项荟萃分析来检验这一假设。多中心病例对照研究将欧洲血液和骨髓移植组（EBMT）数据库中的CML患者与全球骨髓捐献者登记处的未受影响个体进行了比较。患者和对照按国家进行匹配。荟萃分析包括文献中报道的五项研究。由1899名患者和512363名骨髓捐献者作为对照组成的多中心病例对照研究得出，HLA-A3的比值比（OR）为0.90（95%置信区间[CI]，0.8至1），HLA-A11的OR为1.16（95%CI，1.02至1.33），HLA-B8的OR为0.73（95%CI，0.65至0.82）。HLA-A3和HLA-B8的共表达产生的OR为0.51（95%CI，0.4至0.67）。这可以转化为HLA-B8的保护作用为27%，HLA-A3为10%，HLA-A3和HLA-B8组合的保护作用为49%。包含463名CML患者和4912名对照的荟萃分析显示，表达HLA-B8的个体风险降低29%（OR为0.71；95%CI，0.52至0.97），但HLA-A3的OR为1.19（95%CI，0.9至1.56），HLA-A11的OR为1.09（95%CI，0.8至1.5）。总之，这些结果表明HLA-B8表达，特别是当与HLA-A3共表达时，与CML发病率降低有关。一种生物学机制可能是这些HLA分子中bcr-abl断裂点肽的呈递可诱导保护性免疫反应。
