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Blood, 1 January 2008, Vol. 111, No. 1, pp. 112-121. Prepublished online as a Blood First Edition Paper on September 21, 2007; DOI 10.1182/blood-2006-07-037572. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-07-037572v1 111/1/112    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Buitenhuis, M. Articles by Coffer, P. J. Search for Related Content PubMed PubMed Citation Articles by Buitenhuis, M. Articles by Coffer, P. J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 27, 2006 Accepted August 25, 2007 Protein kinase B (C-AKT) regulates hematopoietic lineage choice decisions during myelopoiesis Miranda Buitenhuis, Liesbeth P. Verhagen, Hanneke W.M. van Deutekom, Anders Castor, Sandra Verploegen, Leo Koenderman, Sten-Eirik W. Jacobsen, and Paul J. Coffer* Molecular Immunology Lab, Dept. of Immunology, University Medical Center Utrecht, Utrecht, Netherlands Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund, Sweden Genmab, Utrecht, Netherlands Department of Pulmonary Diseases, University Medical Center Utrecht, Utrecht, Netherlands * Corresponding author; email: p.j.coffer{at}umcutrecht.nl. Hematopoiesis is a highly regulated process resulting in the formation of all blood lineages. Aberrant regulation of phosphatidylinositol-3-kinase (PI3K) signalling has been observed in hematopoietic malignancies, suggesting that regulated PI3K signalling is critical for regulation of blood cell production. An ex vivo differentiation system was utilized 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 2-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/EBP on Thr222/226 was abrogated upon PKB activation in hematopoietic progenitors. Ectopic expression of a non-phosphorylatable C/EBP mutant inhibited eosinophil differentiation ex-vivo, whereas neutrophil development was induced, demonstrating the importance of PKB mediated C/EBP phosphorylation in regulation of granulopoiesis. These results identify an important novel role for PKB in regulation of cell fate choices during hematopoietic lineage commitment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Jacquel, N. Benikhlef, J. Paggetti, N. Lalaoui, L. Guery, E. K. Dufour, M. Ciudad, C. Racoeur, O. Micheau, L. Delva, et al. Colony-stimulating factor-1-induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing differentiation into macrophages Blood, October 22, 2009; 114(17): 3633 - 3641. [Abstract] [Full Text] [PDF] J. M. Moreno-Navarrete, F. J. Ortega, J. Bassols, W. Ricart, and J. M. Fernandez-Real Decreased Circulating Lactoferrin in Insulin Resistance and Altered Glucose Tolerance as a Possible Marker of Neutrophil Dysfunction in Type 2 Diabetes J. Clin. Endocrinol. Metab., October 1, 2009; 94(10): 4036 - 4044. [Abstract] [Full Text] [PDF] L. M. Starnes, A. Sorrentino, E. Pelosi, M. Ballarino, O. Morsilli, M. Biffoni, S. Santoro, N. Felli, G. Castelli, M. L. De Marchis, et al. NFI-A directs the fate of hematopoietic progenitors to the erythroid or granulocytic lineage and controls {beta}-globin and G-CSF receptor expression Blood, August 27, 2009; 114(9): 1753 - 1763. [Abstract] [Full Text] [PDF] C. R. Geest, M. Buitenhuis, E. Vellenga, and P. J. Coffer Ectopic expression of C/EBP{alpha} and ID1 is sufficient to restore defective neutrophil development in low-risk myelodysplasia Haematologica, August 1, 2009; 94(8): 1075 - 1084. [Abstract] [Full Text] [PDF] C. R. Geest, F. J. Zwartkruis, E. Vellenga, P. J. Coffer, and M. Buitenhuis Mammalian target of rapamycin activity is required for expansion of CD34+ hematopoietic progenitor cells Haematologica, July 1, 2009; 94(7): 901 - 910. [Abstract] [Full Text] [PDF] K. Fukushima, I. Matsumura, S. Ezoe, M. Tokunaga, M. Yasumi, Y. Satoh, H. Shibayama, H. Tanaka, A. Iwama, and Y. Kanakura FIP1L1-PDGFR{alpha} Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells J. Biol. Chem., March 20, 2009; 284(12): 7719 - 7732. [Abstract] [Full Text] [PDF] Y. Jia, F. Loison, H. Hattori, Y. Li, C. Erneux, S.-Y. Park, C. Gao, L. Chai, L. E. Silberstein, S. Schurmans, et al. Inositol trisphosphate 3-kinase B (InsP3KB) as a physiological modulator of myelopoiesis PNAS, March 25, 2008; 105(12): 4739 - 4744. [Abstract] [Full Text] [PDF]

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