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Immunobiology

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

Leukemia volume 14, pages 859–862 (2000)Cite this article

Abstract

CML is characterized by the chromosomal translocation t(9;22) (q34;q11) resulting in the chimeric bcr-abl oncogene that encodes P210 fusion proteins with novel amino acid sequences in the breakpoint region. If these peptides derived from P210 are presented by 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 revealed that some peptides 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. Moreover T cell responses have been induced against bcr-abl-derived synthetic peptides bound to some of these HLA molecules. For HLA class I, we have previously 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 molecules we performed a large multi-center study. This study compared the frequencies 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 registry of Bone Marrow Donors Worldwide (n = 500 596). Patients and controls were matched per country. This analysis yielded significantly lower odds ratios (ORs) of 0.86 (95% CI 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 assess a possible effect of the linkage disequilibrium between HLA-B8 and HLA-DR3 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 disequilibrium with HLA-B8. In contrast, as there is no linkage disequilibrium of HLA-DR4 with HLA-A3 or HLA-B8, the results indicate that HLA-DR4 expression itself is associated with a diminished incidence of CML possibly by the presentation of bcr-abl breakpoint peptides in these HLA molecules on the membrane of the leukemic cells.

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Authors and Affiliations

  1. Department of Hematology, Leiden University Medical Center, The Netherlands

    EFM Posthuma, JHF Falkenburg & R Willemze

  2. Department of Haematology, Royal Postgraduate Medical School, London, UK

    JF Apperley

  3. Division of Hematology, Department of Internal Medicine, Kantonsspital Basel, Switzerland

    A Gratwohl

  4. Medizinische Hochschule, Hannover, Germany

    B Hertenstein

  5. Department of Immunohematology, Leiden University Medical Center, The Netherlands

    RF Schipper

  6. Department of Europdonor Foundation, The Netherlands

    M Oudshoorn

  7. Department of Medical Statistics, Leiden University Medical Center, The Netherlands

    JH v Biezen & J Hermans

  8. Hopital Cantonal Universitaire de Geneve, Switzerland

    E Roosnek

  9. Abteilung Hämatologie, Universitat Leipzig, Leipzig, Germany

    D Niederwieser

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  1. EFM Posthuma
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  2. JHF Falkenburg
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  10. R Willemze
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on behalf of the Chronic Leukemia Working Party of the European Blood and Marrow Transplant Registry

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Posthuma, E., Falkenburg, J., Apperley, J. et al. HLA-DR4 is associated with a diminished risk of the development of chronic myeloid leukemia (CML). Leukemia 14, 859–862 (2000). https://doi.org/10.1038/sj.leu.2401774

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