HLA-DPB1 supertype-associated protection from childhood leukaemia: relationship to leukaemia karyotype and implications for prevention |
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Authors: | Malcolm Taylor Christine Harrison Tim Eden Jillian Birch Mel Greaves Tracy Lightfoot Adiba Hussain |
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Institution: | (1) Cancer Immunogenetics Laboratory, St Mary’s Hospital, University of Manchester, Manchester, M13 0JH, UK;(2) Leukaemia Research Fund Cytogenetics Group, Cancer Sciences Division, Southampton General Hospital, University of Southampton, Southampton, UK;(3) Teenage Cancer Trust Young Oncology Unit, Christie Hospital, University of Manchester, Manchester, UK;(4) CR UK Paediatric and Familial Cancer Research Group, Royal Manchester Children’s Hospital, University of Manchester, Manchester, UK;(5) Institute for Cancer Research, Section of Haemato-Oncology, Brookes-Lawley Building, Sutton, Surrey, UK;(6) Epidemiology and Genetics Unit, University of York, York, UK |
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Abstract: | Most childhood B cell precursor (BCP) acute lymphoblastic leukaemia (ALL) cases carry the reciprocal translocation t(12;21)(p13;q22)
(∼25%), or a high hyperdiploid (HeH) karyotype (30%). The t(12;21) translocation leads to the expression of a novel fusion
gene, TEL-AML1 (ETV6-RUNX1), and HeH often involves tri- and tetrasomy for chromosome 21. The presence of TEL-AML1+ and HeH cells in utero prior to the development of leukaemia suggests that these lesions play a critical role in ALL initiation.
Based on our previous analysis of HLA-DP in childhood ALL, and evidence from in vitro studies that TEL-AML1 can activate HLA-DP-restricted T cell responses, we hypothesised that the development of TEL-AML1+ ALL might be influenced by the child’s DPB1 genotype. To test this, we analysed the frequency of six HLA-DPB1 supertypes in a population-based series of childhood leukaemias (n = 776) classified by their karyotype (TEL-AML1+, HeH and others), in comparison with newborn controls (n = 864). One DPB1 supertype (GKD) conferred significant protection against TEL-AML1+ ALL (odds ratio (OR), 95% confidence interval (95% CI): 0.42, 0.22–0.81; p < 0.005) and HeH ALL (OR; 95% CI: 0.44, 0.30–0.65; p < 0.0001). These negative associations were almost entirely due to a single allele, DPB1*0101. Our results suggest that DPB1*0101 may afford protection from the development of TEL-AML1+ and HeH BCP ALL, possibly as the result of a DP-restricted immune response to BCP ALL-associated antigen(s), the identification
of which could have important implications for the design of prophylactic vaccines. |
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Keywords: | HLA -DPB1 Childhood leukaemia Immune response Karyotype TEL-AML1 Hyperdiploidy Prevention |
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