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Blood, 19 March 2009, Vol. 113, No. 12, pp. 2661-2672. Prepublished online as a Blood First Edition Paper on January 23, 2009; DOI 10.1182/blood-2008-06-161117. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2008-06-161117v1 113/12/2661    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tipping, A. J. Articles by Enver, T. Search for Related Content PubMed PubMed Citation Articles by Tipping, A. J. Articles by Enver, T. Related Collections Hematopoiesis and Stem Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle Alex J. Tipping1, Cristina Pina1, Anders Castor2, Dengli Hong1, Neil P. Rodrigues1, Lorenza Lazzari3, Gillian E. May1, Sten Eirik W. Jacobsen2,4, and Tariq Enver1 1 Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; 2 Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden; 3 Cell Factory, Center for Transfusion Medicine, Cellular Therapy and Cryobiology, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy; and 4 Haematopoietic Stem Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom Evidence suggests the transcription factor GATA-2 is a critical regulator of murine hematopoietic stem cells. Here, we explore the relation between GATA-2 and cell proliferation and show that inducing GATA-2 increases quiescence (G0 residency) of murine and human hematopoietic cells. In human cord blood, quiescent fractions (CD34+CD38–HoechstloPyronin Ylo) express more GATA-2 than cycling counterparts. Enforcing GATA-2 expression increased quiescence of cord blood cells, reducing proliferation and performance in long-term culture-initiating cell and colony-forming cell (CFC) assays. Gene expression analysis places GATA-2 upstream of the quiescence regulator MEF, but enforcing MEF expression does not prevent GATA-2–conferred quiescence, suggesting additional regulators are involved. Although known quiescence regulators p21CIP1 and p27KIP1 do not appear to be responsible, enforcing GATA-2 reduced expression of regulators of cell cycle such as CCND3, CDK4, and CDK6. Enforcing GATA-2 inhibited human hematopoiesis in vivo: cells with highest exogenous expression (GATA-2hi) failed to contribute to hematopoiesis in nonobese diabetic–severe combined immunodeficient (NOD-SCID) mice, whereas GATA-2lo cells contributed with delayed kinetics and low efficiency, with reduced expression of Ki-67. Thus, GATA-2 activity inhibits cell cycle in vitro and in vivo, highlighting GATA-2 as a molecular entry point into the transcriptional program regulating quiescence in human hematopoietic stem and progenitor cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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