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Blood, 9 July 2009, Vol. 114, No. 2, pp. 394-403. Prepublished online as a Blood First Edition Paper on May 1, 2009; DOI 10.1182/blood-2008-11-188714. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-11-188714v1 114/2/394    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 CrossRef Google Scholar Articles by Fukuda, S. Articles by Pelus, L. M. PubMed PubMed Citation Articles by Fukuda, S. Articles by Pelus, L. M. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3 Seiji Fukuda1,2, Pratibha Singh1, Akira Moh1, Mariko Abe2, Edward M. Conway3, H. Scott Boswell4, Seiji Yamaguchi2, Xin-Yuan Fu1, and Louis M. Pelus1 1 Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis; 2 Department of Pediatrics, Shimane University School of Medicine, Shimane, Japan; 3 VIB Vesalius Research Center (VRC), KU Leuven, Leuven, Belgium; and 4 Department of Medicine, Division of Hematology/Oncology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis Internal tandem duplication mutations in the Flt3 tyrosine kinase gene (ITD-Flt3) and overexpression of Survivin are frequently found in patients with acute myeloid leukemia (AML). We investigated whether Survivin mediates the enhanced survival of primary hematopoietic progenitor cells (HPCs) resulting from ITD-Flt3 signaling. Ectopic ITD-Flt3 mutants increased Survivin expression in Ba/F3 cells downstream of PI3-kinase/Akt. Treatment of ITD-Flt3+ human MV4-11 leukemia cells with the ITD-Flt3 inhibitor SU5416 reduced Survivin expression and inhibited cell proliferation. ITD-Flt3 dramatically increased the number of primary mouse marrow c-kit+, Sca-1+, LinNeg cells and colony-forming unit granulocyte-macrophages (CFU-GMs) able to proliferate in the absence of growth factors, whereas Survivin deletion significantly reduced growth factor–independent proliferation and increased apoptosis, which was further accentuated by SU5416. Ectopic ITD-Flt3 reduced differentiation of LinNeg marrow cells cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus stem cell factor, which was partially blocked by Survivin deletion. In addition, Survivin deletion decreased secondary colony formation induced by ITD-Flt3. Dominant-negative (dn)–Survivin delayed development of acute leukemia in mice that received a transplant of Ba/F3 cells expressing ITD-Flt3. These results suggest that Survivin regulates expansion of ITD-Flt3–transformed HPCs with self-renewal capability and development of ITD-Flt3+ acute leukemia and that antagonizing Survivin may provide therapeutic benefit for patients with acute leukemia expressing ITD-Flt3. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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