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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3917-3925. Prepublished online as a Blood First Edition Paper on August 16, 2005; DOI 10.1182/blood-2005-04-1424. This Article Full Text (PDF) All Versions of this Article: 2005-04-1424v1 106/12/3917    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 Kerbauy, D. M Articles by Deeg, H J Search for Related Content PubMed PubMed Citation Articles by Kerbauy, D. M Articles by Deeg, H J Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 7, 2005 Accepted July 25, 2005 NF-B and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes (MDS) Daniella M Kerbauy, Vladimir Lesnikov, Nissa Abbasi, Sudeshna Seal, Bart Scott, and H J Deeg* Fred Hutchinson Cancer Research Center, Seattle, WA, USA Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Washington School of Medicine, Seattle, WA, USA * Corresponding author; email: jdeeg{at}fhcrc.org; blarson@fhcrc.org. Tumor necrosis factor (TNF)-, a potent stimulus of NF-B, is upregulated in myelodysplasia (MDS). Here, we show that bone marrow mononuclear cells (BMMC) and purified CD34+ cells from patients with low grade/early stage MDS (RA/RARS) have low levels of NF-B activity in nuclear extracts comparable to normal marrow, while patients with RA with excess blasts (RAEB) show significantly increased levels of activity (P=0.008). Exogenous TNF- enhanced NF-B nuclear translocation in MDS BMMC above baseline levels. Treatment with arsenic trioxide (ATO; 2-200 µM) inhibited NF-B activity in normal marrow, primary MDS, and ML1 cells, even in the presence of exogenous TNF- (20 ng/mL), and downregulated NF-B-dependent anti-apoptotic proteins, Bcl-XL, Bcl-2, XIAP, and FLIP, leading to apoptosis. However, overexpression of FLIP resulted in increased NF-B activity and rendered ML1 cells resistant to ATO-induced apoptosis. These data are consistent with the observed upregulation of FLIP and resistance to apoptosis with advanced MDS where ATO as a single agent may show only limited efficacy. However, the data also suggest that combinations of ATO with agents that interfere with other pathways, such as FLIP autoamplification via NF-B, may have considerable therapeutic activity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. J. Mhyre, A. M. Marcondes, E. Y. Spaulding, and H. J. Deeg Stroma-dependent apoptosis in clonal hematopoietic precursors correlates with expression of PYCARD Blood, January 15, 2009; 113(3): 649 - 658. [Abstract] [Full Text] [PDF] B. Dolniak, E. Katsoulidis, N. Carayol, J. K. Altman, A. J. Redig, M. S. Tallman, T. Ueda, R. Watanabe-Fukunaga, R. Fukunaga, and L. C. Platanias Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2 J. Biol. Chem., May 2, 2008; 283(18): 12034 - 12042. [Abstract] [Full Text] [PDF] A. M. Marcondes, A. J. Mhyre, D. L. Stirewalt, S.-H. Kim, C. A. Dinarello, and H. J. Deeg Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function PNAS, February 26, 2008; 105(8): 2865 - 2870. [Abstract] [Full Text] [PDF] B. C. Bornhauser, L. Bonapace, D. Lindholm, R. Martinez, G. Cario, M. Schrappe, F. K. Niggli, B. W. Schafer, and J.-P. Bourquin Low-dose arsenic trioxide sensitizes glucocorticoid-resistant acute lymphoblastic leukemia cells to dexamethasone via an Akt-dependent pathway Blood, September 15, 2007; 110(6): 2084 - 2091. [Abstract] [Full Text] [PDF] D. Cilloni, G. Martinelli, F. Messa, M. Baccarani, and G. Saglio Nuclear factor {kappa}B as a target for new drug development in myeloid malignancies Haematologica, September 1, 2007; 92(9): 1224 - 1229. [Abstract] [Full Text] [PDF] P. Kannan-Thulasiraman, E. Katsoulidis, M. S. Tallman, J. S. C. Arthur, and L. C. Platanias Activation of the Mitogen- and Stress-activated Kinase 1 by Arsenic Trioxide J. Biol. Chem., August 11, 2006; 281(32): 22446 - 22452. [Abstract] [Full Text] [PDF] T.-C. Lee, I-C. Ho, W.-J. Lu, and J.-d. Huang Enhanced Expression of Multidrug resistance-associated Protein 2 and Reduced Expression of Aquaglyceroporin 3 in an Arsenic-resistant Human Cell Line J. Biol. Chem., July 7, 2006; 281(27): 18401 - 18407. [Abstract] [Full Text] [PDF]

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