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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3863-3865
HLA-B8 and HLA-A3 Coexpressed With HLA-B8 Are Associated With a Reduced
Risk of the Development of Chronic Myeloid Leukemia
E.F.M. Posthuma,
J.H.F. Falkenburg,
J.F. Apperley,
A. Gratwohl,
E. Roosnek,
B. Hertenstein,
R.F. Schipper,
G.M.T. Schreuder,
J. D'Amaro,
M. Oudshoorn,
J.H. v Biezen,
J. Hermans,
R. Willemze, and
D. Niederwieser on behalf of the Chronic Leukemia Working Party of the
EBMT
From the Departments of Hematology, Immunohematology, and Medical
Statistics, Leiden University Medical Center and Europdonor Foundation,
Leiden, The Netherlands; Abteilung Hamatologie, Universitat Leipzig,
Leipzig, Germany; the Division of Hematology, the
Department of Internal Medicine, Kantonsspital Basel, Basel,
Switzerland; Hopital Cantonal Universitaire de Geneve, Geneve,
Switzerland; Medizinische Hochschule, Hannover, Germany;
and the Department of Haematology, Royal Postgraduate Medical School,
London, UK.
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.
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