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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4650-4658. Prepublished online as a Blood First Edition Paper on February 24, 2004; DOI 10.1182/blood-2003-08-2759. This Article Full Text (PDF) All Versions of this Article: 2003-08-2759v1 103/12/4650    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 Takahashi, S. Articles by Licht, J. D Search for Related Content PubMed PubMed Citation Articles by Takahashi, S. Articles by Licht, J. D Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted August 13, 2003 Accepted February 14, 2004 The Flt3 Internal Tandem Duplication Mutant Inhibits the Function of Transcriptional Repressors by Blocking Interactions with SMRT Shinichiro Takahashi, Melanie J McConnell, Hideo Harigae, Mitsuo Kaku, Takeshi Sasaki, Ari M Melnick, and Jonathan D Licht* Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA; Department of Molecular Diagnostics, Tohoku University School of Medicine, Sendai, Miyagi, Japan Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA Department of Molecular Diagnostics, Tohoku University School of Medicine, Sendai, Miyagi, Japan Department of Rheumatology and Hematology, Tohoku University School of Medicine, Sendai, Miyagi, Japan Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, NY, USA * Corresponding author; email: jonathan.licht{at}mssm.edu. Flt3 is a type III receptor tyrosine kinase (RTK). Between 20 and 30% of acute myeloid leukemia (AML) patients have either an internal tandem duplication (ITD) of the juxtamembrane region or a point mutation of the Flt3 receptor leading to the constitutive activation of downstream signaling pathways and aberrant cell growth. The SMRT co-repressor mediates transcriptional repression by interacting with transcription factors such as the PLZF protein. Previous reports indicate that SMRT interaction with transcription factors can be disrupted by phosphorylation through activation of RTK pathways. We report here that the Flt3-ITD interferes with the transcriptional and biological action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited and PLZF mediated growth suppression of leukemia cells was partially blocked. Furthermore, over-expression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. Nuclear export was dependent on the SMRT receptor interaction domain (RID) and Flt3-ITD enhances the binding of nuclear-cytoplasm shuttling protein NFB-p65 to this region. These data suggest that activating mutations of Flt3 may disrupt transcriptional repressor function resulting in aberrant gene regulation and abnormal leukemia cell growth. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: SMRT interactions, repression, and Flt3-ITD Leonidas C. Platanias Blood 2004 103: 4382. [Full Text] [PDF] This article has been cited by other articles: J. L. Hess and B. A. Hug Fusion-protein truncation provides new insights into leukemogenesis PNAS, December 7, 2004; 101(49): 16985 - 16986. [Full Text] [PDF]

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