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Blood, 1 January 2005, Vol. 105, No. 1, pp. 341-349. Prepublished online as a Blood First Edition Paper on August 31, 2004; DOI 10.1182/blood-2004-03-1074. This Article Full Text (PDF) All Versions of this Article: 2004-03-1074v1 105/1/341    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 Glasow, A. Articles by Zelent, A. Search for Related Content PubMed PubMed Citation Articles by Glasow, A. Articles by Zelent, A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 22, 2004 Accepted August 18, 2004 Retinoids and myelomonocytic growth factors co-operatively activate RAR and induce human myeloid leukemia cell differentiation via MAP kinase pathways Annegret Glasow, Natasha Prodromou, Ke Xu, Marieke von Lindern, and Arthur Zelent* Section of Hematological Oncology, Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom Department of Hematology, Erasmus MC, Rotterdam, The Netherlands * Corresponding author; email: arthur.zelent{at}icr.ac.uk. Use of all-trans-retinoic acid (ATRA) in combinatorial differentiation therapy of acute promyelocytic leukemia (APL) results in exceptional cure rates. However, potent cell differentiation effects of ATRA are so far largely restricted to this disease and long-term survival rates in non-APL acute myelogeneous leukemia (AML) remain unacceptably poor, requiring development of novel therapeutic strategies. We demonstrate here that myelomonocytic growth factors (G-CSF and/or GM-CSF) potentiate differentiation effects of ATRA in different AML cell lines as well as primary cells from patients with myeloid leukemia. The ligand dependent activities of endogenous and transiently expressed retinoic acid receptor alpha (RAR) isoforms can be potentiated by G/GM-CSF in U-937 cells and correlate with increased expression of ATRA inducible RAR2 isoform. Specific inhibitors of MEK-1/-2 or p38 mitogen activated protein (MAP) kinase diminish the ATRA as well as ATRA and G/GM-CSF induced activation of the RAR proteins and decreased the differentiation-induced decline in cell numbers. Our data demonstrate that acting, at least in part, via the MAP kinase pathways, myelomonocytic growth factors enhance ATRA dependent activation of the RAR isoforms as well as maturation of myeloid leukemia cells. These results suggest that combinatorial use of these agents may be effective in differentiation therapy of AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Zhang, L.-P. Song, Y. Huang, Q. Zhao, K.-W. Zhao, and G.-Q. Chen Accumulation of hypoxia-inducible factor-1{alpha} protein and its role in the differentiation of myeloid leukemic cells induced by all-trans retinoic acid Haematologica, October 1, 2008; 93(10): 1480 - 1487. [Abstract] [Full Text] [PDF] A. Glasow, A. Barrett, K. Petrie, R. Gupta, M. Boix-Chornet, D.-C. Zhou, D. Grimwade, R. Gallagher, M. von Lindern, S. Waxman, et al. 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Padula, et al. Sequential Valproic Acid/All-trans Retinoic Acid Treatment Reprograms Differentiation in Refractory and High-Risk Acute Myeloid Leukemia. Cancer Res., September 1, 2006; 66(17): 8903 - 8911. [Abstract] [Full Text] [PDF] K. Xu, F. Guidez, A. Glasow, D. Chung, K. Petrie, K. Stegmaier, K.-K. Wang, J. Zhang, Y. Jing, A. Zelent, et al. Benzodithiophenes Potentiate Differentiation of Acute Promyelocytic Leukemia Cells by Lowering the Threshold for Ligand-Mediated Corepressor/Coactivator Exchange with Retinoic Acid Receptor {alpha} and Enhancing Changes in all-trans-Retinoic Acid-Regulated Gene Expression Cancer Res., September 1, 2005; 65(17): 7856 - 7865. [Abstract] [Full Text] [PDF]

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