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. Boswell, Seiji Yamaguchi, Xin Yuan Fu, Louis Pelus

Research output: Contribution to journalArticle

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Abstract

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 ITDFlt3 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 granulocytemacrophages (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 ITDFlt3. 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.

Original languageEnglish
Pages (from-to)394-403
Number of pages10
JournalBlood
Volume114
Issue number2
DOIs
StatePublished - 2009

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Cell proliferation
Hematopoietic Stem Cells
Intercellular Signaling Peptides and Proteins
Leukemia
Cells
Cell Proliferation
Transplants
Stem Cell Factor
Granulocyte-Macrophage Colony-Stimulating Factor
Phosphatidylinositol 3-Kinases
Protein-Tyrosine Kinases
Genes
Bone Marrow
Apoptosis
Acute Myeloid Leukemia
Cultured Cells
Stem Cells
Mutation
Semaxinib
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3. / Fukuda, Seiji; Singh, Pratibha; Moh, Akira; Abe, Mariko; Conway, Edward M.; Boswell, H.; Yamaguchi, Seiji; Fu, Xin Yuan; Pelus, Louis.

In: Blood, Vol. 114, No. 2, 2009, p. 394-403.

Research output: Contribution to journalArticle

Fukuda, Seiji ; Singh, Pratibha ; Moh, Akira ; Abe, Mariko ; Conway, Edward M. ; Boswell, H. ; Yamaguchi, Seiji ; Fu, Xin Yuan ; Pelus, Louis. / Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3. In: Blood. 2009 ; Vol. 114, No. 2. pp. 394-403.
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abstract = "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 ITDFlt3 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 granulocytemacrophages (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 ITDFlt3. 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.",
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AU - Fukuda, Seiji

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AU - Conway, Edward M.

AU - Boswell, H.

AU - Yamaguchi, Seiji

AU - Fu, Xin Yuan

AU - Pelus, Louis

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N2 - 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 ITDFlt3 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 granulocytemacrophages (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 ITDFlt3. 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.

AB - 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 ITDFlt3 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 granulocytemacrophages (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 ITDFlt3. 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.

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