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Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model.

Reckzeh, Kristian LU ; Bereshchenko, O; Mead, A; Rehn, Matilda LU ; Kharazi, Shabnam LU ; Jacobsen, Sten Eirik W LU ; Nerlov, Claus and Cammenga, Jörg LU (2012) In Leukemia 26(7). p.1527-1536
Abstract
Biallelic CEBPA mutations and FLT3 length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear due to a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed C/EBPα mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMP) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPα mutations. These cellular... (More)
Biallelic CEBPA mutations and FLT3 length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear due to a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed C/EBPα mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMP) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPα mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors (MPP) and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.Leukemia accepted article preview online, 9 February 2012; doi:10.1038/leu.2012.37. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Leukemia
volume
26
issue
7
pages
1527 - 1536
publisher
Nature Publishing Group
external identifiers
  • wos:000306307600012
  • pmid:22318449
  • scopus:84863775829
ISSN
1476-5551
DOI
10.1038/leu.2012.37
language
English
LU publication?
yes
id
bcc53010-0370-417a-abc9-7040db352fe9 (old id 2367144)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22318449?dopt=Abstract
date added to LUP
2012-03-02 10:32:53
date last changed
2017-11-12 03:44:44
@article{bcc53010-0370-417a-abc9-7040db352fe9,
  abstract     = {Biallelic CEBPA mutations and FLT3 length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear due to a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed C/EBPα mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMP) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPα mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors (MPP) and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.Leukemia accepted article preview online, 9 February 2012; doi:10.1038/leu.2012.37.},
  author       = {Reckzeh, Kristian and Bereshchenko, O and Mead, A and Rehn, Matilda and Kharazi, Shabnam and Jacobsen, Sten Eirik W and Nerlov, Claus and Cammenga, Jörg},
  issn         = {1476-5551},
  language     = {eng},
  number       = {7},
  pages        = {1527--1536},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model.},
  url          = {http://dx.doi.org/10.1038/leu.2012.37},
  volume       = {26},
  year         = {2012},
}