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Modeling of C/EBP alpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells

Kirstetter, Peggy; Schuster, Mikkel B.; Bereshchenko, Oksana; Moore, Susan; Dvinge, Heidi; Kurz, Elke; Theilgaard-Monch, Kim; Månsson, Robert LU ; Pedersen, Thomas A. and Pabst, Thomas, et al. (2008) In Cancer Cell 13(4). p.299-310
Abstract
Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBP alpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1(+)c-Kit(+) population that gave rise only to myeloid cells in recipient mice. Expression... (More)
Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBP alpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1(+)c-Kit(+) population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1(+)c-Kit(+) progenitors revealed a signature shared with MLL-AF9-transformed AML. (Less)
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Contribution to journal
publication status
published
subject
in
Cancer Cell
volume
13
issue
4
pages
299 - 310
publisher
Cell Press
external identifiers
  • wos:000254817400005
  • scopus:41249103144
ISSN
1878-3686
DOI
10.1016/j.ccr.2008.02.008
language
English
LU publication?
yes
id
15af4b25-43a1-4126-9ec1-c6b496ce5155 (old id 1207328)
date added to LUP
2008-08-27 14:34:50
date last changed
2017-11-12 03:26:29
@article{15af4b25-43a1-4126-9ec1-c6b496ce5155,
  abstract     = {Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBP alpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1(+)c-Kit(+) population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1(+)c-Kit(+) progenitors revealed a signature shared with MLL-AF9-transformed AML.},
  author       = {Kirstetter, Peggy and Schuster, Mikkel B. and Bereshchenko, Oksana and Moore, Susan and Dvinge, Heidi and Kurz, Elke and Theilgaard-Monch, Kim and Månsson, Robert and Pedersen, Thomas A. and Pabst, Thomas and Schrock, Evelin and Porse, Bo T. and Jacobsen, Sten Eirik W and Bertone, Paul and Tenen, Daniel G. and Nerlov, Claus},
  issn         = {1878-3686},
  language     = {eng},
  number       = {4},
  pages        = {299--310},
  publisher    = {Cell Press},
  series       = {Cancer Cell},
  title        = {Modeling of C/EBP alpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells},
  url          = {http://dx.doi.org/10.1016/j.ccr.2008.02.008},
  volume       = {13},
  year         = {2008},
}