Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201

Abstract

In a previous study, we obtained preliminary evidence in a small series of patients (n = 63) suggesting that susceptibility to childhood common acute lymphoblastic leukaemia (c-ALL) was associated with an allele at the HLA-DPB1 locus, DPB1*0201. We have now tested this hypothesis by comparing the frequency of children with leukaemia (n = 982) who typed for specific DPB1 alleles and two groups of non-leukaemic children, one consisting of children with solid tumours, excluding lymphomas (n = 409), the other consisting of normal infants (n = 864). We found that significantly more children with c-ALL and T-ALL, but not pro-B ALL or acute non-ALL typed for DPB1*0201 as compared with children with solid tumours [odds ratio (OR), 95% confidence interval (CI) for c-ALL: 1.76, 1.20-2.56; T-ALL: 1.93, 1.01-3.80] and normal infants (OR, 95% CI for c-ALL: 1.83, 1.34-2.48; T-ALL: 2.00, 1.10-3.82). In childhood c-ALL, significantly more children than those with solid tumours or normal infants typed for DPB1 alleles coding specific polymorphic amino acids lining the antigen-binding site of the DPbeta1*0201 allotypic protein, suggesting that susceptibility to childhood c-ALL may be influenced by DPbeta ABS amino acid polymorphisms shared by DPbeta1*0201 and other DPbeta1 allotypes. These results point to a mechanism of c-ALL susceptibility that involves the presentation of specific antigenic peptides, possibly derived from infectious agents, by DPbeta1*0201-related allotypic proteins, leading to the activation of helper T cells mediating proliferative stress on preleukaemic cells.

A combined DPA1∼DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer

“…Likewise, anti-DP antibodies appear to play an important role in kidney transplant outcomes (Singh et al 2010; Thaunat et al 2009). In addition, numerous studies suggest that DPB1 is associated with predisposition to infectious disease such as hepatitis B (Howell and Visvanathan 2009; Kamatani et al 2009), autoimmune disorders such as multiple sclerosis (Begovich et al 1990; Odum et al 1988) and juvenile idiopathic arthritis (Hollenbach et al 2010), and leukemia (Taylor et al 2002). The very strong evidence for a role of DPB1 in development of chronic beryllium disease (CBD; Amicosante et al 2001; Fontenot et al 2000; Lombardi et al 2001) suggests that despite low levels of cell surface expression, antigen presentation by the DP molecule is capable of stimulating a robust and clinically significant immune response.…”

Differences in Meiotic Recombination Rates in Childhood Acute Lymphoblastic Leukemia at an MHC Class II Hotspot Close to Disease Associated Haplotypes

“…In view of our results suggesting weak associations between certain HLA-DPB1 alleles and childhood BCP-ALL [14], [16], [22], recent evidence [18] that an MHC SNP most strongly associated with childhood ALL (rs3135034) is approximately 97 kb telomeric of HLA-DPB1 , and a significant association of ALL cases in the Northern California Childhood Leukemia Study (NCCLS) with rs9296068, located approximately 60 kb telomeric from HLA-DPB1, we considered that these SNPs might be in LD with BCP-ALL-associated HLA-DPB1 alleles.…”

“…Clues provided by evidence that susceptibility to mouse retroviral ALL is linked to the MHC [11], and that certain human leukocyte antigen (HLA) alleles are associated with susceptibility to specific infections (reviewed in [12]), have encouraged the search for HLA allele associations with childhood ALL as a proxy for infection [13], [14], [15], [16], [17]. Previous studies of the HLA-DPB1 locus which identified multiple, though weak, allele associations with ALL suggested a role for common antigenic peptide binding pockets in susceptibility.…”

SNP Association Mapping across the Extended Major Histocompatibility Complex and Risk of B-Cell Precursor Acute Lymphoblastic Leukemia in Children

“…HLA - A , - B , and - C , and HLA-DP , - DQ , and - DR ). The most consistent evidence of an association has been for HLA class II loci, including HLA-DPB1 [10,12] and HLA-DR [8,35], genes relatively close in proximity to rs9296068 and HLA-DOA . However, due to the lack of genetic characterization of the surrounding regions in these studies, it could not be unambiguously determined whether those associations indicated a causal link with the HLA gene or whether the associations were an effect of LD with an adjacent causal locus.…”

“…Despite evidence of linkage between predisposition to retrovirus-induced leukemia and the murine MHC, attempts to identify associations between childhood ALL and classical HLA alleles have been inconsistent largely due to study design limitations [8,9,10,11,12]. Although these have been largely overcome by the application of high-resolution HLA molecular genotyping to carefully ascertained case-control series, strong and replicable associations have yet to emerge.…”