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Blood, 15 October 2003, Vol. 102, No. 8, pp. 2969-2975. Prepublished online as a Blood First Edition Paper on July 3, 2003; DOI 10.1182/blood-2002-12-3813. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-12-3813v1 102/8/2969    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 Minami, Y. Articles by Naoe, T. Search for Related Content PubMed PubMed Citation Articles by Minami, Y. Articles by Naoe, T. Related Collections Neoplasia Apoptosis Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia Yosuke Minami, Kazuhito Yamamoto, Hitoshi Kiyoi, Ryuzo Ueda, Hidehiko Saito, and Tomoki Naoe From the Department of Hematology, Nagoya University Graduate School of Medicine, Nagoya, Japan; the Department of Infectious Diseases, Nagoya University School of Medicine, Nagoya, Japan; the Second Department of Internal Medicine, Nagoya City University School of Medicine, Nagoya, Japan; and the Department of Medicine, Nagoya National Hospital, Nagoya, Japan. An internal tandem duplication (ITD) of the juxtamembrane (JM) domain of FLT3 (FLT3/ITD) has been found in 20% of patients with acute myeloid leukemia (AML) and is correlated with leukocytosis and a poor prognosis. Here, we compared the antiapoptotic effects of wild-type FLT3 (WtFLT3) and FLT3/ITD in terms of the regulation of Bcl-2 family members. In a murine myeloid cell line, 32D, interleukin-3 (IL-3) deprivation induced apoptosis following the down-regulation of Bcl-XL and the dephosphorylation of Bad. However, the expression levels of Bcl-2, Bax, Bak, and Mcl-1 were unchanged. In WtFLT3-transfected 32D (WtFLT3-32D) cells, FLT3 ligand (FL) stimulation did not restore the down-regulation of Bcl-XL but maintained the phosphorylation of Bad. Combined treatment with phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, dephosphorylated Bad and induced apoptosis in WtFLT3-32D cells stimulated with FL. Induction of nonphosphorylated Bad induced remarkable apoptosis. These findings suggest that the FL stimulation is associated with antiapoptosis through Bad phosphorylation. On the other hand, FLT3/ITD-transfected 32D (FLT3/ITD-32D) cells survived in an IL-3–or FL-deprived state. Furthermore, the dephosphorylation of Bad using LY294002 and PD98059 was insufficient for apoptosis, and the down-regulation of Bcl-XL using antisense treatment was needed to induce apoptosis. FLT3 kinase inhibitor, AG1296, alone not only dephosphorylated Bad but also down-regulated Bcl-XL, leading FLT3/ITD-32D cells into apoptosis. These findings suggest that the antiapoptotic pathways from FLT3/ITD are more divergent than those from WtFLT3 and may represent targets for drug discovery with the potential of inducing selective cell death of human leukemia cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Shiotsu, H. Kiyoi, Y. Ishikawa, R. Tanizaki, M. Shimizu, H. Umehara, K. Ishii, Y. Mori, K. Ozeki, Y. Minami, et al. 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