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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4326-4333. Prepublished online as a Blood First Edition Paper on February 2, 2006; DOI 10.1182/blood-2005-11-4608. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-11-4608v1 107/11/4326    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wierenga, A. T. J. Articles by Schuringa, J. J. Search for Related Content PubMed PubMed Citation Articles by Wierenga, A. T. J. Articles by Schuringa, J. J. Related Collections Hematopoiesis and Stem Cells Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves down-modulation of C/EBP Albertus T. J. Wierenga, Hein Schepers, Malcolm A. S. Moore, Edo Vellenga, and Jan Jacob Schuringa From the University Medical Center Groningen, Department of Hematology, Groningen, The Netherlands; and Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York, NY. Previously, we demonstrated that enforced activation of signal transducer and activator of transcription 5 (STAT5A) in human cord blood (CB)–derived stem/progenitor cells results in enhanced self-renewal and impaired myelopoiesis. The present study identifies C/EBP as a critical component that is down-regulated by STAT5. Microarray and reverse transcriptase–polymerase chain reaction (RT-PCR) analysis on STAT5A1*6-transduced CD34+ cells identified C/EBP as the most prominently down-regulated gene. To determine the cell-biological relevance of these observations, a 4-OHT-inducible C/EBP-ER protein was co-expressed with the STAT5A1*6 mutant in CB CD34+ cells using a retroviral approach. Re-expression of C/EBP in STAT5A1*6 cells resulted in a marked restoration of myelopoiesis. The proliferative advantage imposed on CD34+ cells by STAT5A1*6 depended on the down-modulation of C/EBP, as reintroduction of C/EBP induced a quick cell-cycle arrest and the onset of myeloid differentiation. Long-term culture–initiating cell (LTC-IC) frequencies were elevated from 0.8% ± 0.6% to 7.8% ± 1.9% by STAT5A1*6 as compared with controls, but these elevated LTC-IC frequencies were strongly reduced upon re-introduction of C/EBP in STAT5A1*6 cells, and no second cobble-stone area–forming cells (CAFCs) could be generated from double-transduced cells. Enumeration of progenitors revealed that the number of colony-forming cells (CFCs) was reduced more than 20-fold when C/EBP was co-expressed in STAT5A1*6 cells. Our data indicate that down-modulation of C/EBP is a prerequisite for STAT5-induced effects on self-renewal and myelopoiesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. G. Olthof, S. Fatrai, A. L. Drayer, M. R. Tyl, E. Vellenga, and J. J. Schuringa Downregulation of Signal Transducer and Activator of Transcription 5 (STAT5) in CD34+ Cells Promotes Megakaryocytic Development, Whereas Activation of STAT5 Drives Erythropoiesis Stem Cells, July 1, 2008; 26(7): 1732 - 1742. [Abstract] [Full Text] [PDF] S. Boehrer, L. Ades, T. Braun, L. Galluzzi, J. Grosjean, C. Fabre, G. Le Roux, C. Gardin, A. Martin, S. de Botton, et al. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study Blood, February 15, 2008; 111(4): 2170 - 2180. [Abstract] [Full Text] [PDF] H. Schepers, D. van Gosliga, A. T. J. Wierenga, B. J. L. Eggen, J. J. Schuringa, and E. Vellenga STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells Blood, October 15, 2007; 110(8): 2880 - 2888. [Abstract] [Full Text] [PDF] H. Schepers, A. T. J. Wierenga, D. van Gosliga, B. J. L. Eggen, E. Vellenga, and J. J. Schuringa Reintroduction of C/EBP{alpha} in leukemic CD34+ stem/progenitor cells impairs self-renewal and partially restores myelopoiesis Blood, August 15, 2007; 110(4): 1317 - 1325. [Abstract] [Full Text] [PDF] C. Choudhary, C. Brandts, J. Schwable, L. Tickenbrock, B. Sargin, A. Ueker, F.-D. Bohmer, W. E. Berdel, C. Muller-Tidow, and H. Serve Activation mechanisms of STAT5 by oncogenic Flt3-ITD Blood, July 1, 2007; 110(1): 370 - 374. [Abstract] [Full Text] [PDF] K. Y. Chung, G. Morrone, J. J. Schuringa, M. Plasilova, J.-H. Shieh, Y. Zhang, P. Zhou, and M. A.S. Moore Enforced Expression of NUP98-HOXA9 in Human CD34+ Cells Enhances Stem Cell Proliferation Cancer Res., December 15, 2006; 66(24): 11781 - 11791. [Abstract] [Full Text] [PDF]

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