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Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11.2 is mediated by a CEBPE promoter polymorphism

Studd, James B.; Yang, Minjun LU ; Li, Zhenhua; Vijayakrishnan, Jayaram; Lu, Yi; Yeoh, Allen Eng Juh; Paulsson, Kajsa LU and Houlston, Richard S. (2019) In Leukemia 33(1). p.1-14
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),... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Leukemia
volume
33
issue
1
pages
1 - 14
publisher
Nature Publishing Group
external identifiers
  • scopus:85049574790
ISSN
0887-6924
DOI
10.1038/s41375-018-0184-z
language
English
LU publication?
yes
id
48b1b0c4-bec4-444e-9a2f-e53778b745a2
date added to LUP
2018-07-23 09:33:19
date last changed
2019-01-22 03:00:10
@article{48b1b0c4-bec4-444e-9a2f-e53778b745a2,
  abstract     = {<p>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&gt;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.</p>},
  author       = {Studd, James B. and Yang, Minjun and Li, Zhenhua and Vijayakrishnan, Jayaram and Lu, Yi and Yeoh, Allen Eng Juh and Paulsson, Kajsa and Houlston, Richard S.},
  issn         = {0887-6924},
  language     = {eng},
  number       = {1},
  pages        = {1--14},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11.2 is mediated by a CEBPE promoter polymorphism},
  url          = {http://dx.doi.org/10.1038/s41375-018-0184-z},
  volume       = {33},
  year         = {2019},
}