Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia

Dorak, M. Tevfik, Lawson, T., Machulla, H. K., Darke, C., Mills, K. I. and Burnett, Alan Kenneth 1999. Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia. Blood 94 (2) , pp. 694-700.

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	American Society of Hematology
ISSN:	0006-4971
Last Modified:	25 Jun 2017 04:42
URI:	https://orca.cardiff.ac.uk/id/eprint/58747

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