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Blood, 23 April 2009, Vol. 113, No. 17, pp. 4052-4062. Prepublished online as a Blood First Edition Paper on January 14, 2009; DOI 10.1182/blood-2008-05-156422. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2008-05-156422v1 113/17/4052    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Zhou, J. Articles by Chen, C.-S. Search for Related Content PubMed PubMed Citation Articles by Zhou, J. Articles by Chen, C.-S. Related Collections Myeloid Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML Jianbiao Zhou1, Chonglei Bi1, Jasinghe V. Janakakumara1, Shaw-Cheng Liu1, Wee-Joo Chng13, Kian-Ghee Tay1, Lai-Fong Poon1, Zhigang Xie1, Senthilnathan Palaniyandi1, Hanry Yu4,5, Keith B. Glaser6, Daniel H. Albert6, Steven K. Davidsen6, and Chien-Shing Chen1,2,7 1 Department of Medicine and 2 Oncology Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 3 Department of Hematology-Oncology, National University Hospital, Singapore; 4 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 5 Institute of Biotechnology and Nanotechnology, A*STAR, Singapore; 6 Abbott Laboratories, Chicago, IL; and 7 Division of Hematology and Oncology School of Medicine, Loma Linda University, CA To further investigate potential mechanisms of resistance to FLT3 inhibitors, we developed a resistant cell line by long-term culture of MV4-11 cells with ABT-869, designated as MV4-11-R. Gene profiling reveals up-regulation of FLT3LG (FLT3 ligand) and BIRC5 (survivin), but down-regulation of SOCS1, SOCS2, and SOCS3 in MV4-11-R cells. Hypermethylation of these SOCS genes leads to their transcriptional silencing. Survivin is directly regulated by STAT3. Stimulation of the parental MV4-11 cells with FLT3 ligand increases the expression of survivin and phosphorylated protein STAT1, STAT3, STAT5. Targeting survivin by short-hairpin RNA (shRNA) in MV4-11-R cells induces apoptosis and augments ABT-869–mediated cytotoxicity. Overexpression of survivin protects MV4-11 from apoptosis. Subtoxic dose of indirubin derivative (IDR) E804 resensitizes MV4-11-R to ABT-869 treatment by inhibiting STAT signaling activity and abolishing survivin expression. Combining IDR E804 with ABT-869 shows potent in vivo efficacy in the MV4-11-R xenograft model. Taken together, these results demonstrate that enhanced activation of STAT pathways and overexpression of survivin are important mechanisms of resistance to ABT-869, suggesting that the STAT pathways and survivin could be potential targets for reducing resistance developed in patients receiving FLT3 inhibitors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Fathoming Flt3 Roger Briesewitz Blood 2009 113: 3889-3890. [Full Text] [PDF] This article has been cited by other articles: R. Briesewitz Fathoming Flt3 Blood, April 23, 2009; 113(17): 3889 - 3890. [Full Text] [PDF]

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