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Prepublished online as a Blood First Edition Paper on July 25, 2002August 1, 2002; DOI 10.1182/blood-2002-05-1602. This Article Full Text (PDF) All Versions of this Article: 2002-05-1602v1 2002-05-1602v2 100/12/3983    most recent Alert me when this article is cited Alert me if a correction is posted 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 Bradley, H. L Articles by Bunting, K. D Search for Related Content PubMed PubMed Citation Articles by Bradley, H. L Articles by Bunting, K. D Social Bookmarking                   What's this? Submitted May 31, 2002 Accepted July 3, 2002 Cell intrinsic defects in cytokine responsiveness of STAT5-deficient hematopoietic stem cells Heath L Bradley, Teresa S Hawley, and Kevin D Bunting* Hematopoiesis Department, American Red Cross Holland Laboratory, Rockville, MD, USA Hematopoiesis Department, American Red Cross Holland Laboratory, Rockville, MD, USA; Flow Cytometry Facility, American Red Cross Holland Laboratory, Rockville, MD, USA Hematopoiesis Department, American Red Cross Holland Laboratory, Rockville, MD, USA; Anatomy and Cell Biology Department, The George Washington University, Washington, DC, USA; Anatomy and Cell Biology Department, The George Washington University, Washington, DC, USA * Corresponding author; email: buntingk{at}usa.redcross.org. Secreted growth factors are integral components of the bone marrow (BM) niche and can regulate survival, proliferation, and differentiation of committed hematopoietic stem cells (HSCs). However, downstream genes activated in HSCs by early acting cytokines are not well characterized. To better define intracellular cytokine signaling in HSC function, we have analyzed mice lacking expression of both STAT5a and STAT5b (STAT5ab-/-). These studies specifically avoided possible autoimmune and/or splenomegaly disease-mediated indirect effects on HSC function by using two independent approaches; 1) crossing onto the C57Bl/6 RAG2-/- background and 2) generation of wild-type transplanted chimeric mice reconstituted with STAT5ab-/- BM cells. These experiments demonstrated that STAT5-deficient HSCs have cell autonomous defects in competitive long-term repopulating activity. Furthermore, in the chimeric mice, injected wild-type BM cells showed a progressive multilineage competitive repopulating advantage in vivo, demonstrating that steady-state hematopoiesis was also highly STAT5-dependent. Consistent with the in vivo repopulating deficiency, when Sca-1+c-kit+lin- (KLS) cells were isolated and stimulated with growth factors in vitro, up to a 13-fold reduced expansion of total nucleated cells was observed in response to cocktails containing interleukin (IL)-3, IL-6, stem cell factor (SCF), Flt3 ligand, and thrombopoietin. Notably, a 10-fold reduction in expansion was observed with IL-3 and SCF. However, STAT5 activation was not required for regeneration of the KLS pool in vivo following transplant or for secondary repopulating ability. These studies support a major role for STAT5 activation as a cellular determinant of cytokine-mediated HSC repopulating potential but not self-renewal capacity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Zeoli, P. Dentelli, A. Rosso, G. Togliatto, A. Trombetta, L. Damiano, P. F. di Celle, L. Pegoraro, F. Altruda, and M. F. 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