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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1832-1843. Prepublished online as a Blood First Edition Paper on June 24, 2008; DOI 10.1182/blood-2007-12-130138. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-12-130138v1 112/5/1832    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 Cohen, P. A. Articles by Shu, S. Search for Related Content PubMed PubMed Citation Articles by Cohen, P. A. Articles by Shu, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 19, 2007 Accepted May 22, 2008 STAT3- and STAT5-dependent pathways competitively regulate the pan-differentiation of CD34pos cells into tumor-competent dendritic cells Peter A. Cohen*, Gary K. Koski, Brian J. Czerniecki, Kevin D. Bunting, Xin-Yuan Fu, Zhengqi Wang, Wen-Jun Zhang, Charles S. Carter, Mohamed Awad, Christopher A. Distel, Hassan Nagem, Christopher C. Paustian, Terrence D. Johnson, John F. Tisdale, and Suyu Shu Center for Surgery Research, Cleveland Clinic, Cleveland, OH, United States Department of Surgery, University of Pennsylvania Medical Center, Philadelphia, PA, United States Hematology/Oncology, Case Comprehensive Cancer Center, Cleveland, OH, United States Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, United States Department of Transfusion Medicine, NIH, Bethesda, MD, United States National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, United States * Corresponding author; email: cohenp{at}ccf.org. The clinical outcomes of dendritic cell (DC)-based immunotherapy remain disappointing, with DCs often displaying a tenuous capacity to complete maturation and DC1 polarization in the tumor host. Surprisingly, we observed that the capacity for successful DC1 polarization, including robust IL12p70 production, could be regulated by STAT-dependent events even prior to DC differentiation. Exposure of CD34pos cells to single agent GMCSF induced multilineage, STAT5-dependent differentiation, including DCs which failed to mature in the absence of further exogenous signals. In contrast, Flt3L induced nearly global differentiation of CD34pos cells into spontaneously maturing DCs. IL-6 synergized with Flt3L to produce explosive, STAT3-dependent proliferation of phenotypically undifferentiated cells which nevertheless functioned as committed DC1 precursors. Such precursors not only resisted many tumor associated immunosuppressants, but also responded to tumor contact or TGF with facilitated DC maturation and IL12p70 production, and displayed a superior capacity to reverse tumor induced T-cell tolerance. GMCSF preempted Flt3L or Flt3L+IL6 licensing by blocking STAT3 activation and promoting STAT5 dependent differentiation. Paradoxically, following overt DC differentiation, STAT5 enhanced whereas STAT3 inhibited DC1 polarization. Therefore, non-overlapping, sequential activation of STAT3 and STAT5, achievable by sequenced exposure to Flt3L+IL6, then GMCSF, selects for multilog expansion, programming and DC1 polarization of tumor-competent DCs from CD34pos cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Schmidt-Arras, S.-A. Bohmer, S. Koch, J. P. Muller, L. Blei, H. Cornils, R. Bauer, S. Korasikha, C. Thiede, and F.-D. Bohmer Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality Blood, April 9, 2009; 113(15): 3568 - 3576. [Abstract] [Full Text] [PDF]

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