Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201.
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.
Taylor
G Malcolm
GM
Immunogenetics Laboratory, St Mary's Hospital, Manchester M13 0JH, UK. gmtaylor@man.ac.uk
Dearden
Simon
S
Ravetto
Paul
P
Ayres
Michelle
M
Watson
Pamela
P
Hussain
Adiba
A
Greaves
Mel
M
Alexander
Freda
F
Eden
Osborn B
OB
D001665:Binding Sites; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit; D004171:Diploidy; D005260:Female; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics* / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006579:Heterozygote; D006801:Humans; D007223:Infant; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012016:Reference Values; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D015514:Oncogene Proteins, Fusion; D010455:Peptides; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein