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

Alex J. Tipping, Cristina Pina, Anders Castor, Dengli Hong, Neil P. Rodrigues, Lorenza Lazzari, Gillian E. May, Sten Eirik W Jacobsen, Tariq Enver

Research output: Contribution to journalArticle

67 Citations (Scopus)

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 (G0 residency) of murine and human hematopoietic cells. In human cord blood, quiescent fractions (CD34+CD38-Hoechst 10Pyronin Y10) express more GATA-2 than cycling counterparts. Enforcing GATA-2 expression increased quiescence of cord blood cells, reducing proliferation and performance in longterm 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-210 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 languageEnglish
Pages (from-to)2661-2672
Number of pages12
JournalBlood
Volume113
Issue number12
DOIs
Publication statusPublished - Mar 19 2009

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Hematopoietic Stem Cells
Cell Cycle
Cells
GATA2 Transcription Factor
Hematopoiesis
Blood
Fetal Blood
Cell Proliferation
Cell proliferation
Stem cells
Cell culture
Gene expression
SCID Mice
Assays
Internship and Residency
Blood Cells
Kinetics
Cell Culture Techniques
Gene Expression

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. / Tipping, Alex J.; Pina, Cristina; Castor, Anders; Hong, Dengli; Rodrigues, Neil P.; Lazzari, Lorenza; May, Gillian E.; Jacobsen, Sten Eirik W; Enver, Tariq.

In: Blood, Vol. 113, No. 12, 19.03.2009, p. 2661-2672.

Research output: Contribution to journalArticle

Tipping, AJ, Pina, C, Castor, A, Hong, D, Rodrigues, NP, Lazzari, L, May, GE, Jacobsen, SEW & Enver, T 2009, 'High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle', Blood, vol. 113, no. 12, pp. 2661-2672. https://doi.org/10.1182/blood-2008-06-161117
Tipping, Alex J. ; Pina, Cristina ; Castor, Anders ; Hong, Dengli ; Rodrigues, Neil P. ; Lazzari, Lorenza ; May, Gillian E. ; Jacobsen, Sten Eirik W ; Enver, Tariq. / High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. In: Blood. 2009 ; Vol. 113, No. 12. pp. 2661-2672.
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