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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2303-2310.
Prepublished online as a Blood First Edition Paper on November 10, 2005; DOI 10.1182/blood-2005-07-3005.
 Previous Article | Next Article 
Submitted July 26, 2005
Accepted October 26, 2005
Mammalian target of rapamycin (mTOR) regulates both proliferation of megakaryocyte progenitors and late stages of megakaryocyte differentiation
Hana Raslova*, Veronique Baccini, Lamya Loussaief, Beatrice Comba, Jerome Larghero, Najet Debili, and William Vainchenker
INSERM U362, Institut Gustave Roussy PR1, Villejuif, France
Laboratoire de Biologie Cellulaire Hematopoietique, EMI00-03, Hopital Saint Louis, Paris, France
* Corresponding author; email: hraslova{at}igr.fr.
A major determinant in platelet production is the megakaryocyte (MK) size that is regulated both by ploidization and the increase in cytoplasmic volume at the end of maturation. Here we investigated the involvement of the mTOR pathway in the regulation of megakaryopoiesis. We show that phosphorylation of mTOR, p70S6K1 and 4E-BP1 was diminished in thrombopoietin-cultured human MKs after rapamycin treatment. Rapamycin induced an inhibition in the G1/S transition and a decrease in the mean MK ploidy via a diminution of p21 and cyclin D3 occurring at a transcriptional level. Both cycling (2N/4N) and polyploid MKs (8N/16N) were reduced in size, with a size reduction slightly more pronounced in mature polyploid MKs than in immature one. Rapamycin also induced a delay in the expression of MK markers and prevented the generation of proplatelet MKs. Additional experiments performed in vitro with MKs from mutant mice showed that the decrease in mean ploidy level and the delay in MK differentiation in the presence of rapamycin were less pronounced in p21-/- MKs than in p21+/+ MKs. These findings indicate that the mTOR pathway plays an important role during megakaryopoiesis by regulating ploidy, cell size and maturation, in part by regulating p21 and cyclin D3.
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