Submitted November 12, 2008
Accepted April 24, 2009
Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal-tandem-duplication of Flt3
Seiji Fukuda*, Pratibha Singh, Akira Moh, Mariko Abe, Edward M. Conway, H. Scott Boswell, Seiji Yamaguchi, Xin-Yuan Fu, and Louis M. Pelus
Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, United States
Department of Pediatrics, Shimane University School of Medicine, Izumo, Shimane, Japan
VIB Vesalius Research Center (VRC), KU Leuven, Leuven, Belgium
Department of Medicine, Division of Hematology/Oncology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, United States
* Corresponding author; email: sfukuda{at}med.shimane-u.ac.jp.
Internal-Tandem-Duplication mutations in the Flt3 tyrosine kinase gene (ITD-Flt3) and over-expression 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 (HPC) 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 CFU-GM able to proliferate in the absence of growth factors, while 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 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 transplanted with Ba/F3 cells expressing ITD-Flt3. These results suggest that Survivin regulates expansion of ITD-Flt3-transformed HPC 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.
