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Hematopoietic Stem Cell Expansion Precedes the Generation of Committed Myeloid Leukemia-initiating Cells in C/EBP alpha Mutant AML

Bereshchenko, Oxana; Mancini, Elena; Moore, Susan; Bilbao, Daniel; Månsson, Robert LU ; Luc, Sidinh; Grover, Amit; Jacobsen, Sten Eirik W LU ; Bryder, David LU and Nerlov, Claus (2009) In Cancer Cell 16(5). p.390-400
Abstract
We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBP alpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBP alpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBP alpha mutations incorporates both features,... (More)
We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBP alpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBP alpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBP alpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Cell
volume
16
issue
5
pages
390 - 400
publisher
Cell Press
external identifiers
  • wos:000271755100008
  • scopus:70350497395
ISSN
1878-3686
DOI
10.1016/j.ccr.2009.09.036
language
English
LU publication?
yes
id
70255314-147d-40f7-a2fc-3b5d4e384676 (old id 1519566)
date added to LUP
2009-12-28 12:33:46
date last changed
2017-11-12 03:29:52
@article{70255314-147d-40f7-a2fc-3b5d4e384676,
  abstract     = {We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBP alpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBP alpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBP alpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations.},
  author       = {Bereshchenko, Oxana and Mancini, Elena and Moore, Susan and Bilbao, Daniel and Månsson, Robert and Luc, Sidinh and Grover, Amit and Jacobsen, Sten Eirik W and Bryder, David and Nerlov, Claus},
  issn         = {1878-3686},
  language     = {eng},
  number       = {5},
  pages        = {390--400},
  publisher    = {Cell Press},
  series       = {Cancer Cell},
  title        = {Hematopoietic Stem Cell Expansion Precedes the Generation of Committed Myeloid Leukemia-initiating Cells in C/EBP alpha Mutant AML},
  url          = {http://dx.doi.org/10.1016/j.ccr.2009.09.036},
  volume       = {16},
  year         = {2009},
}