Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia.

Abstract

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.

• Authors: M T Dorak, T Lawson, H K Machulla, C Darke, K I Mills, A K Burnett
• Journal: Blood (Blood) Vol. 94 Issue 2 Pg. 694-700 (Jul 15 1999) ISSN: 0006-4971 [Print] United States
• PMID: 10397736 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Viral
• H-2 Antigens
• H-2E(k) antigen
• HLA-DR Antigens
• HLA-DR53
• HLA-DRB4 Chains
• HSP70 Heat-Shock Proteins

Topics

• Abortion, Habitual (epidemiology)
• Adenoviruses, Human (immunology)
• Adolescent
• Animals
• Antigens, Viral (immunology)
• Child
• Child, Preschool
• Female
• Fetal Blood (immunology)
• Gene Frequency
• Genetic Predisposition to Disease
• Genotype
• H-2 Antigens (genetics, immunology)
• HLA-DR Antigens (genetics, immunology)
• HLA-DRB4 Chains
• HSP70 Heat-Shock Proteins (genetics)
• Herpesvirus 4, Human (immunology)
• Humans
• Infant
• Infant, Newborn
• Leukemia, Experimental (genetics)
• Male
• Mice
• Molecular Mimicry
• Odds Ratio
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (epidemiology, genetics, immunology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (epidemiology, etiology, genetics, immunology)
• Pregnancy
• Risk Factors
• Sex Distribution
• Virus Diseases (complications, immunology)