Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3.
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(+), Lin(Neg) 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 Lin(Neg) 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.
Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, USA. sfukuda@med.shimane-u.ac.jp
Seiji
S
Fukuda
Pratibha
P
Singh
Akira
A
Moh
Mariko
M
Abe
Edward M
EM
Conway
H Scott
HS
Boswell
Seiji
S
Yamaguchi
Xin-Yuan
XY
Fu
Louis M
LM
Pelus
D000208:Acute Disease; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D004789:Enzyme Activation; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins; D000077022:Survivin; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D000077022:Survivin; D019869:Phosphatidylinositol 3-Kinases; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3