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

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.

Vijayakrishnan, JayaramInstitute of Cancer Research London (författare)
Yang, MinjunLund University,Lunds universitet,Aneuploidi i cancer,Forskargrupper vid Lunds universitet,Aneuploidy in cancer,Lund University Research Groups(Swepub:lu)mi3441ya (författare)
Migliorini, GabrieleInstitute of Cancer Research London (författare)
Paulsson, KajsaLund University,Lunds universitet,Aneuploidi i cancer,Forskargrupper vid Lunds universitet,Aneuploidy in cancer,Lund University Research Groups(Swepub:lu)kgen-kpa (författare)
Houlston, Richard S.Institute of Cancer Research London (författare)
Institute of Cancer Research LondonAneuploidi i cancer (creator_code:org_t)

Ingår i:Nature Communications: Springer Science and Business Media LLC82041-1723

Av författaren/redakt...: Studd, James B.; Vijayakrishnan, ...; Yang, Minjun; Migliorini, Gabr ...; Paulsson, Kajsa; Houlston, Richar ...

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