HLA-associated susceptibility to childhood B-cell precursor ALL: definition and role of HLA-DPB1 supertypes

Abstract

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.

HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

“…19 The most common supertype, DP4, was present in a large majority of non-Hispanic white (79.2%) and Hispanic (82.5%) control children. The DP1 supertype, which includes DPB1 alleles *01:01, *05:01, and *50:01, showed elevated ORs and a statistically significant increased risk associated with the high-hyperdiploid ALL subtype (OR ϭ 1.83; 95% CI, 1.20-2.78; P ϭ .005; Table 4).…”

“…18 In addition, DPB1*04:02 was associated with an increased risk, whereas DPB1*01:01 showed a reduced risk. Further investigation of HLA-DPB1 alleles as supertypes indicated a reduced risk associated with DP1 (GKD), 19 which appeared to be driven by the DPB1*01:01 allele. 20 This effect was most marked for TEL-AML1 and high hyperdiploid-positive ALL.…”

“…Twentythree of the 28 observed DPB1 alleles can be clustered into 1 of 6 supertypes described previously by Taylor et al 19 The 6 supertypes were defined by 3 dimorphic amino acid residues in pockets 6, 4, and 1 at positions ␤11, ␤69, and ␤84, respectively, which have been shown to play significant roles in the binding characteristics of the peptide-binding groove. 19,29,30 Three of the supertypes have a positively charged lysine (K) at ␤69, whereas the other 3 have a negatively charged glutamic acid (E). This is accompanied by either a glycine (G) or leucine (L) at ␤11 and a G or an aspartic acid (D) at ␤84.…”

“…18 Further examination of these data as supertypes (a classification based on overlapping peptide binding specificity) showed that childhood ALL risk increased in the presence of DP2 and DP8 supertypes and decreased in the presence of the DP1 supertype. 19,20 In the current analysis, we examined the associations of HLA-DPA1 and DPB1 genetic variation, both independently and jointly with 4 separate proxies indicative of early life immune modulation, including markers for infectious exposures in infancy (presence of older siblings, daycare attendance by age 6 months, and reported ear infections in infancy) and breastfeeding. We focused on non-Hispanic white and Hispanic children enrolled in the Northern California Childhood Leukemia Study (NCCLS), which together compose the majority of the study population.…”

A Case-Only Genome-wide Association Study of Gender- and Age-specific Risk Markers for Childhood Leukemia

“…The HLA region is the most polymorphic region in the human genome, which plays an important role in the regulation of the immune system. Although the role of HLA in ALL etiology is not known, several previous studies suggest the role of HLA in childhood ALL risk with gender differential [123][124][125][206][207][208] . Most of the previously identified HLA associations in childhood ALL are in the HLA class II region.…”