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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2291-2298. Prepublished online as a Blood First Edition Paper on June 1, 2004; DOI 10.1182/blood-2003-05-1745. This Article Full Text (PDF) All Versions of this Article: 2003-05-1745v1 104/8/2291    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 Paulus, J.-M. Articles by Vainchenker, W. Search for Related Content PubMed PubMed Citation Articles by Paulus, J.-M. Articles by Vainchenker, W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 30, 2003 Accepted April 29, 2004 Thrombopoietin responsiveness reflects the number of doublings undergone by megakaryocyte progenitors Jean-Michel Paulus*, Najet Debili, Frederic Larbret, Jack Levin, and William Vainchenker Laboratory of Hematology, CHU du Sart Tilman, University of Liege, Liege, Belgium INSERM U 362, Institut Gustave Roussy, Villejuif, France, Metropolitan Department of Laboratory Medicine, University of California School of Medicine, San Francisco, CA, USA * Corresponding author; email: jmpaulus{at}ulg.ac.be. To assess the variation of thrombopoietin (TPO) responsiveness associated with megakaryocyte (MK) progenitor amplification, TPO dose-response curves were obtained for normal human, single-cell plated CD34+CD41+ cells. The number of MK per well was determined in situ and expressed as number of doublings (NbD). Dose-response curves of the mean frequency of clones of each size vs logTPO concentration showed highly significant differences in the TPO concentration needed for half-maximum generation of clones of different sizes (TPO50): 1.89±0.51 pg/mL for 1 MK clones; 7.75±0.81 for 2-3 MK clones; 38.5±5.04 for 4-7 MK clones and 91.8±16.0 for 8-15 MK clones. These results were consistent with a prediction of the generation-age model, because the number of previous doublings in vivo was inversely correlated with the number of residual doublings in vitro. TPO responsiveness decreased in vitro by a factor of 3.5 per doubling, reflecting the recruitment of progressively more ancestral progenitors. In support of this hypothesis, the more mature CD34+CD41+CD42+ cell fraction had a lower TPO50 (p<0.001), underwent lesser NbD (p<0.001) and expressed a 2.8-fold greater median Mpl receptor density (p<0.001) than the CD34+CD41+CD42- fraction. Progenitors which have completed their proliferative program have maximum factor responsiveness and are preferentially induced to terminal differentiation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Chaligne, C. James, C. Tonetti, R. Besancenot, J. P. Le Couedic, F. Fava, F. Mazurier, I. Godin, K. Maloum, F. Larbret, et al. Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis Blood, November 15, 2007; 110(10): 3735 - 3743. [Abstract] [Full Text] [PDF]

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