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Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-02-0412. This Article Full Text (PDF) All Versions of this Article: 2003-02-0412v1 102/10/3727    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 Park, D. J Articles by Koeffler, H. P. Search for Related Content PubMed PubMed Citation Articles by Park, D. J Articles by Koeffler, H. P. Social Bookmarking                   What's this? Submitted February 7, 2003 Accepted June 22, 2003 Comparative analysis of genes regulated by PML/RAR and PLZF/RAR in response to retinoic acid using oligonucleotide arrays Dorothy J Park*, Peter T Vuong, Sven de Vos, Dan Douer, and H. Phillip Koeffler Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA Division of Hematology/Oncology, Center for Health Sciences, UCLA School of Medicine, Los Angeles, CA, USA Division of Hematology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA * Corresponding author; email: parkd{at}cshs.org. Acute promyelocytic leukemia (APL) is associated with chromosomal translocations involving RAR and its fusion partners including PML and PLZF. Using oligonucleotide arrays, we examined changes in global gene expression mediated by the ectopic expression of either PML/RAR (retinoid-sensitive) or PLZF/RAR (retinoid-resistant) in U937 cells. Of over 5000 genes analyzed, 16 genes were commonly upregulated, and 57 genes were downregulated by both fusion proteins suggesting their role in the APL phenotype. In our APL model, for example, TNFAIP2, TNFR2, ELF4, RAR, and HoxA1 were downregulated by both fusion proteins in the absence of RA. RA strongly upregulated these genes in PML/RAR, but not in PLZF/RAR expressing U937 cells. Expression studies in NB4, retinoid-resistant NB4-R2, normal human CD34+ cells, and APL patient samples strongly suggest their role in the regulation of granulocytic differentiation. Furthermore, combined treatment with TNF and RA synergistically enhanced granulocytic differentiation in NB4 cells but not in NB4-R2 cells. Our data indicate that APL pathogenesis and retinoid-induced granulocytic differentiation of APL cells involve genes in the cell death pathway, and cooperation between the RA and TNF signaling pathways exists. Targeting both the retinoid-dependent differentiation and the cell death pathways may improve leukemic therapy, especially in retinoid-resistant acute myeloid leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Nowak, D. Stewart, and H. P. Koeffler Differentiation therapy of leukemia: 3 decades of development Blood, April 16, 2009; 113(16): 3655 - 3665. [Abstract] [Full Text] [PDF] C. Hoemme, A. Peerzada, G. Behre, Y. Wang, M. McClelland, K. Nieselt, M. Zschunke, C. Disselhoff, S. Agrawal, F. Isken, et al. Chromatin modifications induced by PML-RAR{alpha} repress critical targets in leukemogenesis as analyzed by ChIP-Chip Blood, March 1, 2008; 111(5): 2887 - 2895. 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