Childhood B-cell precursor (BCP) ALL is thought to be caused by a delayed immune response to an unidentified postnatal infection. An association between BCP ALL and HLA class II (DR, DQ, DP) alleles could provide further clues to the identity of the infection, since HLA molecules exhibit allotype-restricted binding of infection-derived antigenic peptides. We clustered 430 HLA-DPB1 alleles into six predicted peptide-binding supertypes (DP1, 2, 3, 4, 6, and 8), based on amino acid di-morphisms at positions 11 (G/L), 69 (E/K), and 84 (G/D) of the DPb 1 domain. We found that the DPb11-69-84 supertype GEG (DP2), was 70% more frequent in BCP ALL (n ¼ 687; Po10 À4 ), and 98% more frequent in cases diagnosed between 3 and 6 years (Po10 À4 ), but not o3 or 46 years, than in controls. Only one of 21 possible DPB1 supergenotypes, GEG/GKG (DP2/DP4) was significantly more frequent in BCP ALL (P ¼ 0.00004) than controls. These results suggest that susceptibility to BCP ALL is associated with the DP2 supertype, which is predicted to bind peptides with positively charged, nonpolar aromatic residues at the P4 position, and hydrophobic residues at the P1 and P6 positions. Studies of peptide binding by DP2 alleles could help to identify infection(s) carrying these peptides.

The extended human major histocompatibility complex (MHC) is a gene-rich region of about 7.6 Mb on chromosome 6, and includes a high proportion of genes involved in the immune response. Among these are the two Human Leukocyte Antigen (HLA) gene clusters, class I and class II, which encode highly polymorphic classical HLA-A, B, C and HLA-DR, DQ and DP genes, respectively. The protein products of the classical HLA genes are heterodimeric cell surface molecules that bind short peptides derived from non-self and self proteins, including infections and auto-antigens. The presentation of these HLA-anchored peptides to T lymphocytes triggers a cascade of responses in immune-associated genes that leads to adaptive immunity. Associations between HLA class II alleles and childhood leukemia have been reported in a number of studies. This could be due to the role of HLA allele-restricted peptide binding and T cell activation, or linkage disequilibrium to an MHC-linked "leukemia gene" in the pathogenesis of childhood leukemia. Efforts are currently in progress to resolve these questions, using large leukemia case-control sample series such as the UK Childhood Cancer Study (UKCCS) and the Northern California Childhood Leukemia Study (NCCLS). Here we review the background to these studies, and present a novel hypothesis based on the paradigm of HLA-associated auto-immune disease that might explain an infection-based etiology of childhood leukemia.

Most childhood B cell precursor (BCP) acute lymphoblastic leukaemia (ALL) cases carry the reciprocal translocation t(12;21)(p13;q22) ( approximately 25%), or a high hyperdiploid (HeH) karyotype (30%). The t(12;21) translocation leads to the expression of a novel fusion gene, TEL-AML1 (ETV6-RUNX1), and HeH often involves tri- and tetrasomy for chromosome 21. The presence of TEL-AML1+ and HeH cells in utero prior to the development of leukaemia suggests that these lesions play a critical role in ALL initiation. Based on our previous analysis of HLA-DP in childhood ALL, and evidence from in vitro studies that TEL-AML1 can activate HLA-DP-restricted T cell responses, we hypothesised that the development of TEL-AML1+ ALL might be influenced by the child's DPB1 genotype. To test this, we analysed the frequency of six HLA-DPB1 supertypes in a population-based series of childhood leukaemias (n = 776) classified by their karyotype (TEL-AML1+, HeH and others), in comparison with newborn controls (n = 864). One DPB1 supertype (GKD) conferred significant protection against TEL-AML1+ ALL (odds ratio (OR), 95% confidence interval (95% CI): 0.42, 0.22-0.81; p < 0.005) and HeH ALL (OR; 95% CI: 0.44, 0.30-0.65; p < 0.0001). These negative associations were almost entirely due to a single allele, DPB1*0101. Our results suggest that DPB1*0101 may afford protection from the development of TEL-AML1+ and HeH BCP ALL, possibly as the result of a DP-restricted immune response to BCP ALL-associated antigen(s), the identification of which could have important implications for the design of prophylactic vaccines.