dc.contributor.author | Studd, JB | |
dc.contributor.author | Yang, M | |
dc.contributor.author | Li, Z | |
dc.contributor.author | Vijayakrishnan, J | |
dc.contributor.author | Lu, Y | |
dc.contributor.author | Yeoh, AE-J | |
dc.contributor.author | Paulsson, K | |
dc.contributor.author | Houlston, RS | |
dc.date.accessioned | 2018-07-10T08:43:06Z | |
dc.date.issued | 2019-01-01 | |
dc.identifier.citation | Leukemia, 2019, 33 (1), pp. 1 - 14 | |
dc.identifier.issn | 0887-6924 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/2008 | |
dc.identifier.eissn | 1476-5551 | |
dc.identifier.doi | 10.1038/s41375-018-0184-z | |
dc.description.abstract | Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Genome-wide association studies have shown variation at 14q11.2 influences ALL risk. We sought to decipher causal variant(s) at 14q11.2 and the mechanism of tumorigenesis. We show rs2239630 G>A resides in the promoter of the CCAT enhancer-binding protein epsilon (CEBPE) gene. The rs2239630-A risk allele is associated with increased promotor activity and CEBPE expression. Depletion of CEBPE in ALL cells reduces cell growth, correspondingly CEBPE binds to the promoters of electron transport and energy generation genes. RNA-seq in CEBPE depleted cells demonstrates CEBPE regulates the expression of genes involved in B-cell development (IL7R), apoptosis (BCL2), and methotrexate resistance (RASS4L). CEBPE regulated genes significantly overlapped in CEBPE depleted cells, ALL blasts and IGH-CEBPE translocated ALL. This suggests CEBPE regulates a similar set of genes in each, consistent with a common biological mechanism of leukemogenesis for rs2239630 associated and CEBPE translocated ALL. Finally, we map IGH-CEBPE translocation breakpoints in two cases, implicating RAG recombinase activity in their formation. | |
dc.format | Print-Electronic | |
dc.format.extent | 1 - 14 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | SPRINGERNATURE | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Tumor Cells, Cultured | |
dc.subject | Chromosomes, Human, Pair 14 | |
dc.subject | Humans | |
dc.subject | Translocation, Genetic | |
dc.subject | Genetic Predisposition to Disease | |
dc.subject | CCAAT-Enhancer-Binding Proteins | |
dc.subject | Microarray Analysis | |
dc.subject | Case-Control Studies | |
dc.subject | Cell Proliferation | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Regulatory Sequences, Nucleic Acid | |
dc.subject | Polymorphism, Genetic | |
dc.subject | Precursor B-Cell Lymphoblastic Leukemia-Lymphoma | |
dc.subject | Promoter Regions, Genetic | |
dc.subject | Epigenomics | |
dc.subject | Biomarkers, Tumor | |
dc.title | Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11.2 is mediated by a CEBPE promoter polymorphism. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-05-30 | |
rioxxterms.versionofrecord | 10.1038/s41375-018-0184-z | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Leukemia | |
pubs.issue | 1 | |
pubs.notes | Not known | |
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 | 33 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Genomics | |
dc.contributor.icrauthor | Studd, James | |
dc.contributor.icrauthor | Vijayakrishnan, Jayaram | |
dc.contributor.icrauthor | Houlston, Richard | |