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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 (G(0) residency) of murine and human hematopoietic cells. In human cord blood, quiescent fractions (CD34(+)CD38(-)Hoechst(lo)Pyronin Y(lo)) 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 p21(CIP1) and p27(KIP1) 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-2(hi)) failed to contribute to hematopoiesis in nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice, whereas GATA-2(lo) 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.

Original publication

DOI

10.1182/blood-2008-06-161117

Type

Journal article

Journal

Blood

Publication Date

19/03/2009

Volume

113

Pages

2661 - 2672

Keywords

Animals, Apoptosis, Cell Cycle, Cells, Cultured, Cord Blood Stem Cell Transplantation, Estradiol, Fetal Blood, GATA2 Transcription Factor, Gene Expression Regulation, Genes, Synthetic, Genes, cdc, Hematopoietic Stem Cells, Humans, Interleukin-3, Mice, Mice, Inbred NOD, Mice, SCID, Receptors, Estrogen, Recombinant Fusion Proteins, Resting Phase, Cell Cycle, Tamoxifen, Transcription, Genetic