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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1693-1701. Prepublished online as a Blood First Edition Paper on November 6, 2003; DOI 10.1182/blood-2002-10-3247. This Article Full Text (PDF) All Versions of this Article: 2002-10-3247v1 103/5/1693    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 Maun, N. A Articles by Berliner, N. Search for Related Content PubMed PubMed Citation Articles by Maun, N. A Articles by Berliner, N. Social Bookmarking                   What's this? Submitted October 28, 2002 Accepted October 29, 2003 G-CSF signaling can differentiate promyelocytes expressing a defective retinoic acid receptor: evidence for divergent pathways regulating neutrophil differentiation Noel A Maun, Peter Gaines, Arati Khanna-Gupta, Theresa Zibello, Louie Enriquez, Laura Goldberg, and Nancy Berliner* Department of Internal Medicine, Section of Hematology, Yale University School of Medicine, New Haven, CT, USA * Corresponding author; email: nancy.berliner{at}yale.edu. Several lines of investigation suggest that G-CSF augments all-trans retinoic acid (ATRA)-induced neutrophil differentiation in acute promyelocytic leukemia (APL). We sought to characterize the relationship between G-CSF- and ATRA-mediated neutrophil differentiation. We established a G-CSF receptor-transduced promyelocytic cell line, EPRO-Gr, derived from the GM-CSF-dependent EPRO cell line harboring a dominant-negative retinoic acid receptor alpha (RAR). In EPRO-Gr, neutrophil differentiation occurs either in GM-CSF upon addition of ATRA, or upon induction with G-CSF alone. Transient transfection of EPRO-Gr cells with a RARE-containing reporter plasmid demonstrates increased activity in the presence of ATRA, but not G-CSF, while STAT3 phosphorylation occurs only in response to G-CSF. This suggests that ATRA-mediated differentiation of EPRO-Gr cells occurs via an RARE-dependent, STAT3-independent pathway, while G-CSF mediated differentiation occurs via an RARE-independent, STAT3-dependent pathway. ATRA and G-CSF thus regulate differentiation by divergent pathways. We characterized these pathways in the APL cell line, NB4. ATRA-induction of NB4 cells resulted in morphologic differentiation and upregulation of C/EBPand G-CSFR, but not in STAT3 phosphorylation. The addition of G-CSF with ATRA during NB4 induction resulted in STAT3 phosphorylation but did not enhance differentiation. These results may elucidate how G-CSF and ATRA affect the differentiation of primary and ATRA-resistant APL cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Shao, X. Xu, N. Jing, and D. J. Tweardy Unique structural determinants for stat3 recruitment and activation by the granulocyte colony-stimulating factor receptor at phosphotyrosine ligands 704 and 744. J. Immunol., March 1, 2006; 176(5): 2933 - 2941. [Abstract] [Full Text] [PDF] E. Villamor and W. W. Fawzi Effects of Vitamin A Supplementation on Immune Responses and Correlation with Clinical Outcomes Clin. Microbiol. Rev., July 1, 2005; 18(3): 446 - 464. [Abstract] [Full Text] [PDF] P. Gaines, J. Chi, and N. Berliner Heterogeneity of functional responses in differentiated myeloid cell lines reveals EPRO cells as a valid model of murine neutrophil functional activation J. Leukoc. Biol., May 1, 2005; 77(5): 669 - 679. [Abstract] [Full Text] [PDF]

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