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Nat Commun. 2017 Mar 3;8:14616. doi: 10.1038/ncomms14616.

Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10p21.2.

Author information

1
Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.
2
Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, BMC C13, Lund SE-221 84, Sweden.
3
Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.

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.

PMID:
28256501
PMCID:
PMC5337971
DOI:
10.1038/ncomms14616
[Indexed for MEDLINE]
Free PMC Article

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