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Protein kinase B (c-akt) regulates hematopoietic lineage choice decisions during myelopoiesis

Buitenhuis, Miranda ; Verhagen, Liesbeth P ; van Deutekom, Hanneke W M ; Castor, Anders LU orcid ; Verploegen, Sandra ; Koenderman, Leo ; Jacobsen, Sten Eirik W LU and Coffer, Paul J (2008) In Blood 111(1). p.112-121
Abstract
Hematopoiesis is a highly regulated process resulting in the formation of all blood lineages. Aberrant regulation of phosphatidylinositol-3-kinase (PI3K) signaling has been observed in hematopoietic malignancies, suggesting that regulated PI3K signaling is critical for regulation of blood cell production. An ex vivo differentiation system was used to investigate the role of PI3K and its downstream effector, protein kinase B (PKB/c-akt) in myelopoiesis. PI3K activity was essential for hematopoietic progenitor survival. High PKB activity was found to promote neutrophil and monocyte development, while, conversely, reduction of PKB activity was required to induce optimal eosinophil differentiation. In addition, transplantation of... (More)
Hematopoiesis is a highly regulated process resulting in the formation of all blood lineages. Aberrant regulation of phosphatidylinositol-3-kinase (PI3K) signaling has been observed in hematopoietic malignancies, suggesting that regulated PI3K signaling is critical for regulation of blood cell production. An ex vivo differentiation system was used to investigate the role of PI3K and its downstream effector, protein kinase B (PKB/c-akt) in myelopoiesis. PI3K activity was essential for hematopoietic progenitor survival. High PKB activity was found to promote neutrophil and monocyte development, while, conversely, reduction of PKB activity was required to induce optimal eosinophil differentiation. In addition, transplantation of beta2-microglobulin (-/-) NOD/SCID mice with CD34(+) cells ectopically expressing constitutively active PKB resulted in enhanced neutrophil and monocyte development, whereas ectopic expression of dominant-negative PKB induced eosinophil development in vivo. Inhibitory phosphorylation of C/EBPalpha on Thr222/226 was abrogated upon PKB activation in hematopoietic progenitors. Ectopic expression of a nonphosphorylatable C/EBPalpha mutant inhibited eosinophil differentiation ex vivo, whereas neutrophil development was induced, demonstrating the importance of PKB-mediated C/EBPalpha phosphorylation in regulation of granulopoiesis. These results identify an important novel role for PKB in regulation of cell fate choices during hematopoietic lineage commitment. (Less)
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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
111
issue
1
pages
112 - 121
publisher
American Society of Hematology
external identifiers
  • pmid:17890457
  • wos:000252002000021
  • scopus:38049185075
ISSN
1528-0020
DOI
10.1182/blood-2006-07-037572
language
English
LU publication?
yes
id
7034fc3d-8ce8-417c-ac67-cbd592815415 (old id 1144444)
date added to LUP
2016-04-01 12:33:26
date last changed
2024-05-22 00:08:32
@article{7034fc3d-8ce8-417c-ac67-cbd592815415,
  abstract     = {{Hematopoiesis is a highly regulated process resulting in the formation of all blood lineages. Aberrant regulation of phosphatidylinositol-3-kinase (PI3K) signaling has been observed in hematopoietic malignancies, suggesting that regulated PI3K signaling is critical for regulation of blood cell production. An ex vivo differentiation system was used to investigate the role of PI3K and its downstream effector, protein kinase B (PKB/c-akt) in myelopoiesis. PI3K activity was essential for hematopoietic progenitor survival. High PKB activity was found to promote neutrophil and monocyte development, while, conversely, reduction of PKB activity was required to induce optimal eosinophil differentiation. In addition, transplantation of beta2-microglobulin (-/-) NOD/SCID mice with CD34(+) cells ectopically expressing constitutively active PKB resulted in enhanced neutrophil and monocyte development, whereas ectopic expression of dominant-negative PKB induced eosinophil development in vivo. Inhibitory phosphorylation of C/EBPalpha on Thr222/226 was abrogated upon PKB activation in hematopoietic progenitors. Ectopic expression of a nonphosphorylatable C/EBPalpha mutant inhibited eosinophil differentiation ex vivo, whereas neutrophil development was induced, demonstrating the importance of PKB-mediated C/EBPalpha phosphorylation in regulation of granulopoiesis. These results identify an important novel role for PKB in regulation of cell fate choices during hematopoietic lineage commitment.}},
  author       = {{Buitenhuis, Miranda and Verhagen, Liesbeth P and van Deutekom, Hanneke W M and Castor, Anders and Verploegen, Sandra and Koenderman, Leo and Jacobsen, Sten Eirik W and Coffer, Paul J}},
  issn         = {{1528-0020}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{112--121}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{Protein kinase B (c-akt) regulates hematopoietic lineage choice decisions during myelopoiesis}},
  url          = {{http://dx.doi.org/10.1182/blood-2006-07-037572}},
  doi          = {{10.1182/blood-2006-07-037572}},
  volume       = {{111}},
  year         = {{2008}},
}