Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11.2 is mediated by a CEBPE promoter polymorphism.
Loading...
Embargo End Date
ICR Authors
Authors
Studd, JB
Yang, M
Li, Z
Vijayakrishnan, J
Lu, Y
Yeoh, AE-J
Paulsson, K
Houlston, RS
Yang, M
Li, Z
Vijayakrishnan, J
Lu, Y
Yeoh, AE-J
Paulsson, K
Houlston, RS
Document Type
Journal Article
Date
2019-01-01
Date Accepted
2018-05-30
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.
Citation
Leukemia, 2019, 33 (1), pp. 1 - 14
Source Title
Publisher
SPRINGERNATURE
ISSN
0887-6924
eISSN
1476-5551
Collections
Research Team
Cancer Genomics