Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia.
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-2(k) 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 x 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.
Department of Haematology, University of Wales College of Medicine, Cardiff, Wales, UK. dorak@cardiff.ac.uk
M T
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Dorak
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Lawson
H K
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Machulla
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Darke
K I
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Mills
A K
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Burnett
D000026:Abortion, Habitual / Q000453:epidemiology; D000260:Adenoviruses, Human / Q000276:immunology; D000293:Adolescent; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005312:Fetal Blood / Q000276:immunology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology*; D059845:HLA-DRB4 Chains; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007942:Leukemia, Experimental / Q000235:genetics; D008297:Male; D051379:Mice; D018716:Molecular Mimicry; D016017:Odds Ratio; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics / Q000276:immunology; D011247:Pregnancy; D012307:Risk Factors; D017678:Sex Distribution; D014777:Virus Diseases / Q000150:complications* / Q000276:immunology
D000956:Antigens, Viral; D006183:H-2 Antigens; C068318:H-2E(k) antigen; D006684:HLA-DR Antigens; C050610:HLA-DR53; D059845:HLA-DRB4 Chains; D018840:HSP70 Heat-Shock Proteins