dc.contributor.author | Studd, JB | |
dc.contributor.author | Vijayakrishnan, J | |
dc.contributor.author | Yang, M | |
dc.contributor.author | Migliorini, G | |
dc.contributor.author | Paulsson, K | |
dc.contributor.author | Houlston, RS | |
dc.date.accessioned | 2017-03-24T14:59:00Z | |
dc.date.issued | 2017-03-03 | |
dc.identifier.citation | Nature communications, 2017, 8 pp. 14616 - ? | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/519 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/ncomms14616 | |
dc.description.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. | |
dc.format | Electronic | |
dc.format.extent | 14616 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Chromosomes, Human, Pair 10 | |
dc.subject | Humans | |
dc.subject | Genetic Predisposition to Disease | |
dc.subject | DNA-Binding Proteins | |
dc.subject | Transcription Factors | |
dc.subject | Sequence Analysis, RNA | |
dc.subject | Epigenesis, Genetic | |
dc.subject | Gene Expression Regulation, Leukemic | |
dc.subject | Diploidy | |
dc.subject | Polymorphism, Single Nucleotide | |
dc.subject | Alleles | |
dc.subject | Child | |
dc.subject | Child, Preschool | |
dc.subject | Core Binding Factor Alpha 3 Subunit | |
dc.subject | Precursor Cell Lymphoblastic Leukemia-Lymphoma | |
dc.subject | Enhancer Elements, Genetic | |
dc.subject | Genetic Variation | |
dc.subject | Genome-Wide Association Study | |
dc.subject | Genetic Loci | |
dc.title | Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10p21.2. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-01-17 | |
rioxxterms.versionofrecord | 10.1038/ncomms14616 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-03-03 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature communications | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics | |
pubs.publication-status | Published | |
pubs.volume | 8 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Cancer Genomics | |
dc.contributor.icrauthor | Studd, James | |
dc.contributor.icrauthor | Vijayakrishnan, Jayaram | |
dc.contributor.icrauthor | Houlston, Richard | |