title: Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10p21.2.
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.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.
authors.forename: James B
authors.identifier: 0000-0002-7157-754X
authors.initials: JB
authors.lastname: Studd
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.
authors.forename: Jayaram
authors.initials: J
authors.lastname: Vijayakrishnan
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, BMC C13, Lund SE-221 84, Sweden.
authors.forename: Minjun
authors.initials: M
authors.lastname: Yang
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Migliorini
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, BMC C13, Lund SE-221 84, Sweden.
authors.forename: Kajsa
authors.identifier: 0000-0001-7950-222X
authors.initials: K
authors.lastname: Paulsson
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.|Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004171:Diploidy; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C503805:ARID5B protein, human; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; C493729:Runx3 protein, human; D014157:Transcription Factors