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

James B Studd,Jayaram Vijayakrishnan,Gabriele Migliorini,Minjun Yang,Richard S Houlston,Kajsa Paulsson

doi:10.1038/ncomms14616

James B Studd, Jayaram Vijayakrishnan + Show 4 more

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https://doi.org/10.1038/ncomms14616

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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.

Highlights

Despite high-hyperdiploid acute lymphoblastic leukaemia (HD-Acute lymphoblastic leukaemia (ALL)) being the most common subgroup of paediatric ALL, its aetiology remains unknown
We show this region physically interacts with the transcription start site of AT rich interactive domain 5B (ARID5B), that alleles of rs7090445 have differential enhancer activity and influence RUNX3 binding
We further prioritized associated variants by assessing their regulatory potential inferred through B-cell specific DNase I hypersensitivity mapping and chromatin immunoprecipitation sequencing (ChIP-seq) experiments in the lymphoblastoid cell line (LCL) GM12878 and ALL blasts from the ENCODE14 and Blueprint[15] projects respectively (Fig. 2, Supplementary Tables 9 and 10)

Summary

Introduction

Despite high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL) being the most common subgroup of paediatric ALL, its aetiology remains unknown. 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. Independent genome-wide association studies (GWAS) demonstrated robust association at a locus in the gene AT rich interactive domain 5B (ARID5B) at 10q21.2 (refs 11,12) Variation at this locus is primarily associated with HD-ALL (refs 11,12), having no impact on the risk of ETV6/RUNX1 translocation positive ALL. Consistent with rs7090445 contributing to ALL leukaemic blasts with the C-risk allele have reduced ARID5B expression and preferentially duplicate the copy of chromosome 10 harbouring this variant

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