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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 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 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 Cohen, P. A. Articles by Shu, S. Search for Related Content PubMed PubMed Citation Articles by Cohen, P. A. Articles by Shu, S. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY STAT3- and STAT5-dependent pathways competitively regulate the pan-differentiation of CD34pos cells into tumor-competent dendritic cells Peter A. Cohen1,2, Gary K. Koski1,2, Brian J. Czerniecki3, Kevin D. Bunting2, Xin-Yuan Fu4, Zhengqi Wang2, Wen-Jun Zhang4, Charles S. Carter5, Mohamed Awad1, Christopher A. Distel1, Hassan Nagem1, Christopher C. Paustian1, Terrence D. Johnson1, John F. Tisdale6, and Suyu Shu1,2 1 Center for Surgery Research, Cleveland Clinic Foundation/Lerner Research Institute, OH; 2 Case Comprehensive Cancer Center, Cleveland, OH; 3 Department of Surgery, University of Pennsylvania Medical Center, Philadelphia; 4 Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis; and 5 Department of Transfusion Medicine and 6 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 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 granulocyte-macrophage colony-stimulating factor (GMCSF) induced multilineage, STAT5-dependent differentiation, including DCs that 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 that nevertheless functioned as committed DC1 precursors. Such precursors not only resisted many tumor-associated immunosuppressants, but also responded to tumor contact or TGFβ with facilitated DC maturation and IL12p70 production, and displayed a superior capacity to reverse tumor-induced T-cell tolerance. GMCSF preempted Flt3L or Flt3L plus IL-6 licensing by blocking STAT3 activation and promoting STAT5-dependent differentiation. Paradoxically, following overt DC differentiation, STAT5 enhanced whereas STAT3 inhibited DC1 polarization. Therefore, nonoverlapping, sequential activation of STAT3 and STAT5, achievable by sequenced exposure to Flt3L plus IL-6, 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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