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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1555-1563. Prepublished online as a Blood First Edition Paper on October 27, 2005; DOI 10.1182/blood-2004-12-4704. This Article Full Text (PDF) All Versions of this Article: 2004-12-4704v1 107/4/1555    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 Carter, B. Z Articles by Andreeff, M. Search for Related Content PubMed PubMed Citation Articles by Carter, B. Z Articles by Andreeff, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 9, 2004 Accepted September 20, 2005 Regulation of survivin expression through Bcr-Abl/MAPK cascade: Targeting survivin overcomes Imatinib resistance and increases Imatinib sensitivity in Imatinib responsive CML cells Bing Z Carter, Duncan Mak, Wendy D Schober, Maria Cabreira-Hansen, Miloslav Beran, Teresa McQueen, Wenjing Chen, and Michael Andreeff* Departments of Blood and Marrow Transplantation and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA * Corresponding author; email: mandreef{at}mdanderson.org. KBM5 cells, derived from a patient with blast crisis Philadelphia chromosome-positive (Ph+) CML, and Imatinib resistant KBM5 (KBM5-STI571) cells were found to express high levels of survivin. Inhibition of Bcr-Abl by Imatinib significantly decreased survivin expression and cell viability in KBM5, but much less so in KBM5-STI571 cells. Inhibition of MEK, downstream of the Bcr-Abl signaling cascade decreased survivin expression and cell viability in both, KBM5 and KBM5-STI571 cells. In addition, downregulation of survivin by a survivin antisense oligonucleotide (Sur-AS-ODN) inhibited cell growth and induced maximal G2M block at 48 hrs, while cell death was observed only at 72 hrs in both KBM5 and KBM5-STI571 cells as shown by Annexin V staining. Further, the combination of Sur-AS-ODN and Imatinib induced more cell death in KBM5 cells than did either treatment alone. Downregulating survivin also decreased CFU in blast crisis CML patient samples. Our data therefore suggest that survivin is regulated by the Bcr-Abl/MAPK cascade in Ph+ CML. The fact that downregulating survivin expression induced cell growth arrest and subsequent cell death regardless of the cell response to Imatinib and enhanced the sensitivity to Imatinib suggest the potential therapeutic utility of this strategy in CML patients, both Imatinib-sensitive and resistant. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Zhou, C. Bi, J. V. Janakakumara, S.-C. Liu, W.-J. Chng, K.-G. Tay, L.-F. Poon, Z. Xie, S. Palaniyandi, H. Yu, et al. Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML Blood, April 23, 2009; 113(17): 4052 - 4062. [Abstract] [Full Text] [PDF] V. J. Lavallard, L. A. Pradelli, A. Paul, M. Beneteau, A. Jacquel, P. Auberger, and J.-E. Ricci Modulation of Caspase-Independent Cell Death Leads to Resensitization of Imatinib Mesylate-Resistant Cells Cancer Res., April 1, 2009; 69(7): 3013 - 3020. [Abstract] [Full Text] [PDF]

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