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Molecular and Cellular Biology, November 2008, p. 6668-6680, Vol. 28, No. 21
0270-7306/08/$08.00+0     doi:10.1128/MCB.01025-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels{triangledown} ,{dagger}

Albertus T. J. Wierenga, Edo Vellenga, and Jan Jacob Schuringa*

University Medical Center Groningen, University of Groningen, Department of Hematology, Hanzeplein 1, 9700 RB Groningen, The Netherlands

Received 30 June 2008/ Returned for modification 11 August 2008/ Accepted 29 August 2008

The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34+ cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34+ cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.

* Corresponding author. Mailing address: University Medical Center Groningen, University of Groningen, Department of Hematology, Hanzeplein 1, 9700 RB Groningen, The Netherlands. Phone: 31-50-3619391. Fax: 31-50-3614862. E-mail: j.schuringa{at}int.umcg.nl

{triangledown} Published ahead of print on 8 September 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2008, p. 6668-6680, Vol. 28, No. 21
0270-7306/08/$08.00+0     doi:10.1128/MCB.01025-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Huang, X., Sakamoto, H., Ogawa, M. (2009). Thrombopoietin controls proliferation of embryonic multipotent hematopoietic progenitors. GENES CELLS 14: 851-860 [Abstract] [Full Text]  
  • Wang, Z., Li, G., Tse, W., Bunting, K. D. (2009). Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement. Blood 113: 4856-4865 [Abstract] [Full Text]  


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