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Acute Leukemias

Strong association of the HLA-DP6 supertype with childhood leukaemia is due to a single allele, DPB1*0601

Abstract

We previously reported that susceptibility to childhood B cell precursor ALL (BCP ALL) is associated with HLA-DPB1 alleles having glutamic acid (E) rather than lysine (K) in the P4 antigenic peptide-binding pocket. Clustering 90% of DPB1 alleles into DPB69E (DP2, 6, 8) and DPB69K (DP1, 3, 4) supertypes revealed that DP2 and DP8 are associated with BCP ALL, but DP6 is also associated with non-BCP leukaemia. Here, we report that only one of seven alleles with the DP6 supertype (DPB1*0601) is associated with childhood leukaemia (leukaemia vs controls: odds ratio, 95% confidence interval [OR, CI]: 4.6, 2.0–10.4; corrected P=0.019), but not with childhood solid tumours or lymphomas. DPB1*0601 is also significantly associated with leukaemia subtypes, including BCP ALL, Pro-B ALL, T-ALL and AML. DPB1*0601 is significantly over-transmitted (76.9%) from parents to children with BCP ALL (OR; CI: 4.7; 1.01–22.2). Sequencing the coding region of DPB1*0601 revealed an exon 1–4 haplotype [T-DEAV-KIL-RVI] shared with DPB1*0301 and 0901, but no evidence of germline mutations in childhood leukaemia. These results suggest that the DPβ0601 molecule may be functionally involved in childhood leukaemia. Analysis of peptide binding and T-cell activation by DPβ0601-peptide complexes should help determine its role in childhood leukaemia causation.

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Acknowledgements

This study was funded by grants from the Kay Kendall Leukaemia Fund (to GMT), by support from Cancer Research UK (JMB), and by the Leukaemia Research Fund (TL, CJH). We are indebted to the children and families who took part in the UK Childhood Cancer Study for enabling us to carry out this work. We thank J Simpson and Professor E Roman at the Epidemiology & Genetics Unit, University of York for providing diagnostic and other information for UKCCS cases, Mrs R Carter for blood sample documentation and the midwives at St Mary's Hospital, Manchester for cord blood samples. We are grateful to MD Robinson, Dr C Watson, Dr DA Gokhale, SP Dearden for sample processing, and DPB1 typing. A complete list of UKCCS investigators is given in: UK Childhood Cancer Study Investigators. The United Kingdom Childhood Cancer Study: objectives, materials and methods. Br J Cancer 2000; 82: 1073–1102.

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Taylor, G., Hussain, A., Verhage, V. et al. Strong association of the HLA-DP6 supertype with childhood leukaemia is due to a single allele, DPB1*0601. Leukemia 23, 863–869 (2009). https://doi.org/10.1038/leu.2008.374

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