Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia

Genetic and environmental factors play an interactive role in the developme nt 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 fa ctor. Despite extensive efforts, however, no strong evidence comparable to the H-2(k) influence on mouse leukemia has been shown. The number of negati ve serological studies resulted in a loss of interest and consequently, no molecular HLA-DR association study has been published to date. We reconside red the HLA-DR association in childhood ALL in 114 patients from a single c enter and 325 local newborn controls by polymerase chain reaction (PCR) ana lysis of the HLA-DRB1/3/4/5 loci. With conventional analysis, there was a m oderate allelic association with the most common allele in the HLA-DR53 gro up, HLA-DRB1*04 in the whole group that was stronger in males (P = .0005, o dds ratio = 2.9). When the other expressed HLA-DRB loci were examined, homo zygosity 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 g ender showed that ail of these associations were reflections of a male-spec ific increase in homozygosity for HLA-DRB4*01 (32.8% v 4.0%; odds ratio = 1 1.7, 95%: confidence interval [CI] = 4.9 to 28.0; P = 3 x 10(-8)). This hig hly significant result provided the long-suspected evidence for the HLA-DR influence on the development of childhood ALL while confirming the recessiv e nature of the MHC influence on human leukemogenesis as in experimental mo dels. The cross-reactivity between HLA-DR53 and H-2E(k), 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 childh ood ALL. (C) 1999 by The American Society of Hematology.