Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11.2 is mediated by a CEBPE promoter polymorphism.
MetadataShow full item record
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.
Tumor Cells, Cultured
Chromosomes, Human, Pair 14
Genetic Predisposition to Disease
Gene Expression Regulation, Neoplastic
Regulatory Sequences, Nucleic Acid
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Promoter Regions, Genetic
License start date
Leukemia, 2019, 33 (1), pp. 1 - 14
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0
Showing items related by title, author, creator and subject.
Li, N; Johnson, DC; Weinhold, N; Kimber, S; Dobbins, SE; et al. (CELL PRESS, 2017-09-12)Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by ...
Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10p21.2. Studd, JB; Vijayakrishnan, J; Yang, M; Migliorini, G; Paulsson, K; et al. (NATURE PORTFOLIO, 2017-03-03)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. ...
Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. Zeng, C; Guo, X; Long, J; Kuchenbaecker, KB; Droit, A; et al. (BMC, 2016-06-21)BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale ...