Maximal STAT5-induced Proliferation and Self-renewal at Intermediate STAT5 Activity Levels

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2008 Sep 10

PMID 18779318

Citations 52

Authors

Albertus T J Wierenga

Edo Vellenga

Jan Jacob Schuringa

Affiliations

Soon will be listed here.

Abstract

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.

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References

Gouilleux-Gruart V, Gouilleux F, Desaint C, Claisse J, Capiod J, Delobel J . STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. Blood. 1996; 87(5):1692-7. View

Moore M, Dorn D, Schuringa J, Chung K, Morrone G . Constitutive activation of Flt3 and STAT5A enhances self-renewal and alters differentiation of hematopoietic stem cells. Exp Hematol. 2007; 35(4 Suppl 1):105-16. DOI: 10.1016/j.exphem.2007.01.018. View

Schepers H, van Gosliga D, Wierenga A, Eggen B, Schuringa J, Vellenga E . STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells. Blood. 2007; 110(8):2880-8. DOI: 10.1182/blood-2006-08-039073. View

Li G, Wang Z, Zhang Y, Kang Z, Haviernikova E, Cui Y . STAT5 requires the N-domain to maintain hematopoietic stem cell repopulating function and appropriate lymphoid-myeloid lineage output. Exp Hematol. 2007; 35(11):1684-94. PMC: 2134320. DOI: 10.1016/j.exphem.2007.08.026. View

Pabst T, Mueller B, Zhang P, Radomska H, Narravula S, Schnittger S . Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet. 2001; 27(3):263-70. DOI: 10.1038/85820. View

Ye D, Wolff N, Li L, Zhang S, Ilaria Jr R . STAT5 signaling is required for the efficient induction and maintenance of CML in mice. Blood. 2006; 107(12):4917-25. PMC: 1895818. DOI: 10.1182/blood-2005-10-4110. View

Birkenkamp K, Geugien M, Lemmink H, Kruijer W, Vellenga E . Regulation of constitutive STAT5 phosphorylation in acute myeloid leukemia blasts. Leukemia. 2001; 15(12):1923-31. DOI: 10.1038/sj.leu.2402317. View

Youn B, Mantel C, Broxmeyer H . Chemokines, chemokine receptors and hematopoiesis. Immunol Rev. 2001; 177:150-74. DOI: 10.1034/j.1600-065x.2000.17701.x. View

Schepers H, Wierenga A, van Gosliga D, Eggen B, Vellenga E, Schuringa J . Reintroduction of C/EBPalpha in leukemic CD34+ stem/progenitor cells impairs self-renewal and partially restores myelopoiesis. Blood. 2007; 110(4):1317-25. DOI: 10.1182/blood-2006-10-052175. View

10.

Ihle J . The Stat family in cytokine signaling. Curr Opin Cell Biol. 2001; 13(2):211-7. DOI: 10.1016/s0955-0674(00)00199-x. View

11.

Pallard C, Gouilleux F, Benit L, Cocault L, Souyri M, Levy D . Thrombopoietin activates a STAT5-like factor in hematopoietic cells. EMBO J. 1995; 14(12):2847-56. PMC: 398403. DOI: 10.1002/j.1460-2075.1995.tb07284.x. View

12.

Schuringa J, Wu K, Morrone G, Moore M . Enforced activation of STAT5A facilitates the generation of embryonic stem-derived hematopoietic stem cells that contribute to hematopoiesis in vivo. Stem Cells. 2004; 22(7):1191-204. DOI: 10.1634/stemcells.2004-0033. View

13.

Carlesso N, Frank D, Griffin J . Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. J Exp Med. 1996; 183(3):811-20. PMC: 2192351. DOI: 10.1084/jem.183.3.811. View

14.

Socolovsky M, Nam H, Fleming M, Haase V, Brugnara C, Lodish H . Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood. 2001; 98(12):3261-73. DOI: 10.1182/blood.v98.12.3261. View

15.

Lacout C, Pisani D, Tulliez M, Gachelin F, Vainchenker W, Villeval J . JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood. 2006; 108(5):1652-60. DOI: 10.1182/blood-2006-02-002030. View

16.

Scheller M, Huelsken J, Rosenbauer F, Taketo M, Birchmeier W, Tenen D . Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol. 2006; 7(10):1037-47. DOI: 10.1038/ni1387. View

17.

Rosenbauer F, Wagner K, Kutok J, Iwasaki H, Le Beau M, Okuno Y . Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet. 2004; 36(6):624-30. DOI: 10.1038/ng1361. View

18.

Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, Meijer J, van Oosterhoud S, van Putten W, Valk P . Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. Hematol J. 2003; 4(1):31-40. DOI: 10.1038/sj.thj.6200216. View

19.

Azam M, Erdjument-Bromage H, Kreider B, Xia M, Quelle F, Basu R . Interleukin-3 signals through multiple isoforms of Stat5. EMBO J. 1995; 14(7):1402-11. PMC: 398225. DOI: 10.1002/j.1460-2075.1995.tb07126.x. View

20.

Hennighausen L, Robinson G . Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev. 2008; 22(6):711-21. PMC: 2394721. DOI: 10.1101/gad.1643908. View