High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1401930
- author
- 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
- organization
- publishing date
- 2009
- 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
- 2016-04-01 11:43:33
- date last changed
- 2022-08-13 06:00:24
@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}},
doi = {{10.1182/blood-2008-06-161117}},
volume = {{113}},
year = {{2009}},
}