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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 694-700
Unravelling an HLA-DR Association in Childhood Acute Lymphoblastic
Leukemia
M. Tevfik Dorak,
Tom Lawson,
Helmut K.G. Machulla,
Chris Darke,
Ken I. Mills, and
Alan K. Burnett
From the Department of Haematology, University of Wales College of
Medicine, Cardiff, Wales, UK.
Genetic and environmental factors play an interactive role in the
development of childhood acute lymphoblastic leukemia (ALL). Since the
demonstration of a major histocompatibility complex (MHC) influence on
mouse leukemia in 1964, an HLA association has been considered as a
possible genetic risk factor. Despite extensive efforts, however, no
strong evidence comparable to the H-2k influence on mouse
leukemia has been shown. The number of negative serological studies
resulted in a loss of interest and consequently, no molecular HLA-DR
association study has been published to date. We reconsidered the
HLA-DR association in childhood ALL in 114 patients from a single
center and 325 local newborn controls by polymerase chain reaction
(PCR) analysis of the HLA-DRB1/3/4/5 loci. With conventional analysis,
there was a moderate allelic association with the most common allele in
the HLA-DR53 group, HLA-DRB1*04, in the whole group that was stronger
in males (P = .0005, odds ratio = 2.9). When the other
expressed HLA-DRB loci were examined, homozygosity for HLA-DRB4*01,
encoding the HLA-DR53 specificity, was increased in patients (21.1%
v 8.3%; odds ratio = 2.9, P = .0005).
Consideration of gender showed that all of these associations were
reflections of a male-specific increase in homozygosity for HLA-DRB4*01
(32.8% v 4.0%; odds ratio = 11.7, 95% confidence interval
[CI] = 4.9 to 28.0; P = 3 × 10 8). This highly significant result provided the
long-suspected evidence for the HLA-DR influence on the development of
childhood ALL while confirming the recessive nature of the MHC
influence on human leukemogenesis as in experimental models. The
cross-reactivity between HLA-DR53 and H-2Ek, extensive
mimicry of the immunodominant epitope of HLA-DR53 by several
carcinogenic viruses, and the extra amount of DNA in the vicinity of
the HLA-DRB4 gene argue for the case that HLA-DRB4*01 may be one of the
genetic risk factors for childhood ALL.
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