Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10q21.2

James B. Studd, Jayaram Vijayakrishnan, Minjun Yang, Gabriele Migliorini, Kajsa Paulsson and Richard S. Houlston ()
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James B. Studd: The Institute of Cancer Research
Jayaram Vijayakrishnan: The Institute of Cancer Research
Minjun Yang: Lund University
Gabriele Migliorini: The Institute of Cancer Research
Kajsa Paulsson: Lund University
Richard S. Houlston: The Institute of Cancer Research

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract Despite high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL) being the most common subgroup of paediatric ALL, its aetiology remains unknown. Genome-wide association studies have demonstrated association at 10q21.2. Here, we sought to determine how this region influences HD-ALL risk. We impute genotypes across the locus, finding the single nucleotide polymorphism rs7090445 highly associated with HD-ALL (P=1.54 × 10−38), and residing in a predicted enhancer element. We show this region physically interacts with the transcription start site of ARID5B, that alleles of rs7090445 have differential enhancer activity and influence RUNX3 binding. RUNX3 knock-down reduces ARID5B expression and rs7090445 enhancer activity. Individuals carrying the rs7090445-C risk allele also have reduced ARID5B expression. Finally, the rs7090445-C risk allele is preferentially retained in HD-ALL blasts consistent with inherited genetic variation contributing to arrest of normal lymphocyte development, facilitating leukaemic clonal expansion. These data provide evidence for a biological mechanism underlying hereditary risk of HD-ALL at 10q21.2.

Date: 2017
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DOI: 10.1038/ncomms14616

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