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 Previous Article | Table of Contents | Next Article 
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
By
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.
 |
ABSTRACT |
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.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
CHRONIC MYELOID leukemia (CML) is a
malignant disease affecting an immature hematopoietic precursor cell.
Previous studies failed to identify an association between class I
antigens and CML1-3 with the exception of a study in which
HLA-A19 appeared potentially protective against the acquisition of
CML.4,5
CML is characterized by the chromosomal t(9;22) translocation resulting
in the chimeric bcr-abl gene that encodes the P210 fusion
protein.6,7 Depending on the exons involved in the breakpoint on chromosomes 9 and 22, variants of this fusion protein may
occur, of which b3a2 and b2a2 are the most frequent, each having a
frequency of about 45% in the patients.8,9 Recent studies
showed that the breakpoint region of the b3a2 protein contains amino
acid sequences with binding motifs for HLA-A3, HLA-A11, and
HLA-B8.10 This indicates that if the b3a2 protein is
processed in the leukemic cell allowing presentation of parts of the
protein in HLA molecules on the cell membrane, a T-cell response
against this fusion protein may occur in individuals expressing HLA-A3,
HLA-A11, or HLA-B8. Cytotoxic T-cell responses have been induced in
vitro by bcr-abl-derived synthetic peptides presented by HLA-A3 or -B8
molecules.11,12 If presentation of the b3a2-specific
peptides occurs in vivo, autologous T-cell responses may be reflected
in diminished frequencies of HLA-A3, -A11, or -B8 in patients with CML
compared with those in normal healthy individuals.
To test this hypothesis we performed a multicenter case-control study
and a meta-analysis comparing HLA frequencies in patients with CML with
those in unaffected individuals.
| |
MATERIALS AND METHODS |
Patients and methods.
A multicenter case-control study and a meta-analysis addressing the
hypothesis whether there are diminished frequencies of HLA -A3, -A11,
or -B8 in CML patients was performed. The frequencies of individuals
coexpressing two of these HLA molecules were also compared between
patients and controls. The same analysis was performed for control
purposes on HLA-A2, an antigen not reported to have a binding motif for
bcr-abl-derived peptides and for HLA-A1, also without a binding motif
for the fusion protein, but in linkage disequilibrium with HLA-B8. To
assess a possible protective effect of the A1B8 haplotype itself, also
the frequencies of the combination HLA-A1 positive/HLA-B8 negative
phenotype and of the combination HLA-A1 negative/HLA-B8 positive
phenotype were compared between patients and controls.
The multicenter case-control study comprised 1,899 patients, consisting
of patients who underwent bone marrow transplantation obtained from the
data base of the Chronic Leukemia Working Party of the European Group
for Blood and Marrow Transplantation (EBMT), restricted to 10 countries
with at least 15 patients, of untransplanted patients from two
centers also contributing to EBMT, and 512,363 controls,
matched per country as present in the Bone Marrow Donors Worldwide
Registries.13-15 All HLA data from the EBMT have been reviewed and checked by one of the authors (D.N.).
The results of studies previously reported in literature were combined
in a meta-analysis. These studies were obtained by searching the
MEDLINE data base and checking references in text books. Studies were
included in which at least the frequencies of the HLA-A3, -A11, (-A1
and -A2), and HLA-B8 typings in CML patients were compared with those
in controls. The meta-analysis consisted of 463 patients with CML and
4,912 controls.
Statistical analysis.
Differences, evaluated through odds ratios (OR) with 95% confidence
interval (CI), were assessed by Woolf-Haldane
analysis.16,17 The ORs of the different studies were
combined in a meta-analysis using as study weights the inverse variance
or precision per study.18 In a similar way, the ORs of the
different countries of the EBMT were combined.
| |
RESULTS |
In the EBMT case-control study, 23% of 1,899 patients and 26% of
512,363 controls were HLA-A3 positive, indicating a 10% reduced risk
for HLA-A3 (OR, 0.90; 95% CI, 0.81 to 1.00). The OR for HLA-A11 was
1.16 (95% CI, 1.02 to 1.33). A total of 18% of 1,899 patients and
23% of 512,363 controls were HLA-B8 positive, resulting in a reduced
risk of 27% for HLA-B8 (OR, 0.73; 95% CI, 0.65 to 0.82) (Table 1). The HLA-A1 frequency was 27% in
patients and 31% in controls, which gives a reduced risk of 17% (OR,
0.83; 95% CI, 0.75 to 0.92), probably due to the linkage
disequilibrium with HLA-B8, as the frequency of HLA-A1 positive/HLA-B8
negative individuals did not differ between patients and controls (OR,
0.95; 95% CI, 0.83 to 1.09), whereas both the frequencies of HLA-A1
negative/HLA-B8 positive and HLA-A1 positive/HLA-B8 positive
individuals were diminished among patients compared with controls (OR,
0.73; 95% CI, 0.58 to 0.92, respectively, OR, 0.75; 95%
CI, 0.66 to 0.86) (Table 2). Combination of
the two protective major histocompatability complex (MHC) molecules
HLA-A3 and -B8 gave an even stronger protective effect of 49% (OR,
0.51; 95% CI, 0.40 to 0.67) against the development of CML
(Table 3). HLA-A2 frequencies did not
differ between patients and controls (Table 1).
The meta-analysis consisted of five different studies and included 463 patients with CML and 4,912 healthy controls
(Table 4). In the meta-analysis, the pooled
estimated OR for HLA-A3 was 1.19 (95% CI, 0.90 to 1.56) and for
HLA-A11 1.09 (95% CI, 0.80 to 1.50). The OR for HLA-B8 was 0.71 (95%
CI, 0.52 to 0.97), which gave a 29% risk reduction on the development
of CML. The OR for HLA-A1 was 0.80 (95% CI, 0.61 to 1.01) and 1.03 for
HLA-A2 (95% CI, 0.82 to 1.30).
| |
DISCUSSION |
Recent in vitro studies have shown that synthetic bcr-abl-derived
peptides can be presented in the context of HLA-A3, -A11, and -B8
molecules and can elicit a T-cell response against these peptides.10-12,19 However, no endogenous processing of
bcr/abl protein resulting in the presentation of the fusion region in the HLA molecules has been demonstrated. We hypothesized that if the
bcr/abl-specific peptides could be processed in vivo in these HLA
molecules, the presence of any of these class I antigens may protect an
individual against the development of this disease. The results of the
multicenter case-control study showed a decreased incidence of
individuals expressing HLA-B8 in the CML patient group, corroborating
the findings of the in vitro studies. The negative asociation with
HLA-B8 was confirmed in the meta-analysis. The HLA-A3 frequency in
patients with CML was lowered only in the very large EBMT case-control
study, but not in the meta-analysis. A recently published epidemiologic
study showed an association between homozygosity for HLA-A3 and early
onset CML.20 However, the strongly diminished incidence of
the combination of HLA-A3/HLA-B8 in patients with CML, as found in the
presented case-control study, indicates a negative association with
both HLA-A3 and HLA-B8.
The discrepancy between the protective effect of HLA-B8 and HLA-A3 and
the absence of effect of HLA-A11 may be explained by the inability of
tumor-specific peptides to bind to HLA-A11. Alternatively, peptides
with binding affinities for HLA-A11 may be processed, but are unable to
elicit an immune response. In the in vitro studies, there were also
differences in peptide binding and sensitivity to specific T-cell lines
between these HLA molecules.10,12
Although immune responses have been reported for both b2a2 and
b3a2-derived peptides in HLA-B8,11 the protective effect of
HLA-B8 and HLA-A3 may be underestimated. In vitro T-cell responses have
been mainly described against b3a2-derived peptides.12,19 If no or only minor effects are present in the subgroup of patients with the b2a2 translocation, an even stronger protective effect of
HLA-A3 and -B8 may be expected for the b3a2 subgroup. Peptides other
than the bcr-abl breakpoint region related may also be immunogenic in
combination with HLA-A3 and HLA-B8.
To analyze whether the negative association of HLA-A1 with CML was due
to the linkage disequilibrium of the HLA-A1B8 haplotype, the
frequencies of HLA-A1 positive/HLA-B8 negative, HLA-A1 negative/HLA-B8 positive, and HLA-A1 positive/HLA-B8 positive individuals were compared
between patients and controls in the EBMT case-control study. In the
EBMT study, the HLA-A1 positive/-B8 negative frequency resulted in an
OR of 0.95 (95% CI, 0.83 to 1.09) for patients with CML, the HLA-A1
negative/-B8 positive frequency gave an OR of 0.73 (95% CI, 0.58 to
0.92) for patients with CML compared with controls, whereas the
HLA-A1/HLA-B8 both positive combination yielded an OR of 0.75 (95% CI,
0.66 to 0.86). These results illustrate the negative association of
HLA-A1 is due to the linkage disequilibrium with HLA-B8.
In summary, the studies presented show a negative association of HLA-B8
and HLA-A3 with CML. The possible mechanism may be that binding of
bcr/abl-derived peptides in these HLA molecules lead to an immune
response resulting in a protective effect against the development of
CML. These findings may have implications for a bcr-abl fusion
protein-based immunotherapeutic approach in HLA-A3 and HLA-B8 positive
patients with CML. It may be possible to generate either an autologous
T-cell immune response against these peptides in vitro using patient
lymphocytes or an allogeneic response using donor lymphocytes. In
vitro-generated T-cell lines with a specificity against breakpoint
specific peptides may be used as part of the treatment of CML.
| |
FOOTNOTES |
Submitted July 30, 1998; accepted January 21, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to E.F.M. Posthuma, MD, Leiden University
Medical Center, Department of Hematology, C2R, PO Box 9600, 2300 RC
Leiden, The Netherlands.
| |
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ABSTRACT
INTRODUCTION