Journal Article

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

G. Malcolm Taylor, Simon Dearden, Paul Ravetto, Michelle Ayres, Pamela Watson, Adiba Hussain, Mel Greaves, Freda Alexander, Osborn B. Eden and UKCCS Investigators

in Human Molecular Genetics

Volume 11, issue 14, pages 1585-1597
Published in print July 2002 | ISSN: 0964-6906
Published online July 2002 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/11.14.1585
Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201

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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 DPβ1*0201 allotypic protein, suggesting that susceptibility to childhood c-ALL may be influenced by DPβ ABS amino acid polymorphisms shared by DPβ1*0201 and other DPβ1 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 DPβ1*0201-related allotypic proteins, leading to the activation of helper T cells mediating proliferative stress on preleukaemic cells.

Journal Article.  10250 words.  Illustrated.

Subjects: Genetics and Genomics

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