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High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle

Tipping, Alex J.; Pina, Cristina; Castor, Anders LU ; Hong, Dengli; Rodrigues, Neil P.; Lazzari, Lorenza; May, Gillian E.; Jacobsen, Sten Eirik W LU and Enver, Tariq (2009) In Blood 113(12). p.2661-2672
Abstract
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... (More)
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. (Blood. 2009;113:2661-2672) (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
113
issue
12
pages
2661 - 2672
publisher
American Society of Hematology
external identifiers
  • wos:000264361800009
  • scopus:63849118537
ISSN
1528-0020
DOI
10.1182/blood-2008-06-161117
language
English
LU publication?
yes
id
fc70e2cc-5aa3-491f-bdb1-94c4ff1f6dca (old id 1401930)
date added to LUP
2009-06-03 14:28:40
date last changed
2017-10-29 03:27:16
@article{fc70e2cc-5aa3-491f-bdb1-94c4ff1f6dca,
  abstract     = {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. (Blood. 2009;113:2661-2672)},
  author       = {Tipping, Alex J. and Pina, Cristina and Castor, Anders and Hong, Dengli and Rodrigues, Neil P. and Lazzari, Lorenza and May, Gillian E. and Jacobsen, Sten Eirik W and Enver, Tariq},
  issn         = {1528-0020},
  language     = {eng},
  number       = {12},
  pages        = {2661--2672},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle},
  url          = {http://dx.doi.org/10.1182/blood-2008-06-161117},
  volume       = {113},
  year         = {2009},
}