Mammalian Target of Rapamycin Is Required for Thrombopoietin‐Induced Proliferation of Megakaryocyte Progenitors

Thrombopoietin (TPO) is a potent regulator of megakaryopoiesis and stimulates megakaryocyte (MK) progenitor expansion and MK differentiation. In this study, we show that TPO induces activation of the mammalian target of rapamycin (mTOR) signaling pathway, which plays a central role in translational...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2006-01, Vol.24 (1), p.105-114
Main Authors: Drayer, A. Lyndsay, Olthof, Sandra G. M., Vellenga, Edo
Format: Article
Language:English
Subjects:
Animals
Antigens, CD34 - metabolism
Cell Cycle - drug effects
Cell Differentiation - drug effects
Cell Proliferation - drug effects
Cells, Cultured
CFU‐Mk
Humans
Megakaryocytes - physiology
Megakaryopoiesis
mTOR
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Signal Transduction
Sirolimus - pharmacology
Stem Cells - physiology
Thrombopoietin - pharmacology
TPO
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Summary:Thrombopoietin (TPO) is a potent regulator of megakaryopoiesis and stimulates megakaryocyte (MK) progenitor expansion and MK differentiation. In this study, we show that TPO induces activation of the mammalian target of rapamycin (mTOR) signaling pathway, which plays a central role in translational regulation and is required for proliferation of MO7e cells and primary human MK progenitors. Treatment of MO7e cells, human CD34+, and primary MK cells with the mTOR inhibitor rapamycin inhibits TPO‐induced cell cycling by reducing cells in S phase and blocking cells in G0/G1. Rapamycin markedly inhibits the clonogenic growth of MK progenitors with high proliferative capacity but does not reduce the formation of small MK colonies. Addition of rapamycin to MK suspension cultures reduces the number of MK cells, but inhibition of mTOR does not significantly affect expression of glycoproteins IIb/IIIa (CD41) and glycoprotein Ib (CD42), nuclear polyploidization levels, cell size, or cell survival. The downstream effectors of mTOR, p70 S6 kinase (S6K) and 4E‐binding protein 1 (4E‐BP1), are phosphorylated by TPO in a rapamycin‐ and LY294002‐sensitive manner. Part of the effect of the phosphatidyl inositol 3‐kinase pathway in regulating megakaryopoiesis may be mediated by the mTOR/S6K/4E‐BP1 pathway. In conclusion, these data demonstrate that the mTOR pathway is activated by TPO and plays a critical role in regulating proliferation of MK progenitors, without affecting differentiation or cell survival.
ISSN:1066-5099
1549-4918
DOI:10.1634/stemcells.2005-0062