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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1759-1767. Prepublished online as a Blood First Edition Paper on October 21, 2004; DOI 10.1182/blood-2004-05-2006. This Article Full Text (PDF) All Versions of this Article: 2004-05-2006v1 105/4/1759    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 Kim, K.-T. Articles by Small, D. Search for Related Content PubMed PubMed Citation Articles by Kim, K.-T. Articles by Small, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 27, 2004 Accepted October 12, 2004 Pim-1 is upregulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival Kyu-Tae Kim, Kristin Baird, Joon-Young Ahn, Paul Meltzer, Michael Lilly, Mark Levis, and Donald Small* Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Cancer Genetics Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, USA Department of Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA * Corresponding author; email: donsmall{at}jhmi.edu. Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 play an important role in leukemogenesis and their presence is associated with poor prognosis in acute myeloid leukemia (AML). To better understand FLT3 signaling in leukemogenesis, we have examined the changes in gene expression induced by FLT3/ITD or constitutively activated wild type FLT3 expression. Microarrays were used with RNA harvested before and after inhibition of FLT3 signaling. Pim-1 was found to be one of the most significantly down-regulated genes upon FLT3 inhibition. Pim-1 is a proto-oncogene and is known to be upregulated by STAT5, which itself is a downstream target of FLT3 signaling. Quantitative PCR (QPCR) confirmed the microarray results and demonstrated approximately 10-fold decreases in Pim-1 expression in response to FLT3 inhibition. Pim-1 protein also decreased rapidly in parallel with decreasing autophosphorylation activity of FLT3. Enforced expression of either the 44kd or 33kd Pim-1 isotypes resulted in increased resistance to FLT3 inhibition mediated cytotoxicity and apoptosis. In contrast, expression of a dominant negative Pim-1 construct accelerated cytotoxicity in response to FLT3 inhibition and inhibited colony growth of FLT3/ITD transformed BaF3 cells. These findings demonstrate that constitutively activated FLT3 signaling upregulates Pim-1 expression in leukemia cells. This upregulation contributes to the proliferative and antiapoptotic pathways induced by FLT3 signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. M. Mumenthaler, P. Y.B. Ng, A. Hodge, D. Bearss, G. Berk, S. Kanekal, S. Redkar, P. Taverna, D. B. Agus, and A. Jain Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes Mol. Cancer Ther., October 1, 2009; 8(10): 2882 - 2893. 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