Cooperative and redundant effects of STAT5 and Ras signaling in BCR/ABL transformed hematopoietic cells

Oncogene. 2001 Sep 13;20(41):5826-35. doi: 10.1038/sj.onc.1204549.


The Akt, Ras and STAT5 signaling pathways have each been linked to transformation of hematopoietic cells by BCR/ABL. However the relative contributions of these signaling pathways to BCR/ABL mediated cytokine-independent survival, proliferation and resistance to DNA damage-induced apoptosis have not been systematically defined. Here we report that activation of either Akt, Ras or STAT5 confers cytokine-independent survival to IL-3 dependent BaF3 cells. Ras or STAT5, but not Akt, also drives cytokine-independent proliferation and imparts sustained resistance to DNA damage-induced apoptosis. We also show that dominant negative (DN) inhibition of STAT5, but not Ras or Akt, significantly reduces resistance to DNA damage-induced apoptosis in BCR/ABL transformed BaF3 cells. Whereas inhibition of STAT5 or Ras alone does not compromise cytokine-independent proliferation of BaF3-BCR/ABL cells, simultaneous blockade of both STAT5 and Ras reduces proliferation and maximally sensitizes BaF3-BCR/ABL cells to DNA damage induced by gamma-irradiation, suggesting a cooperative role for these two signaling pathways in BCR/ABL transformation. The anti-apoptotic properties of BCR/ABL can be partly explained by an increase in the expression of Pim-1 and Bcl-XL, as ectopic expression of these STAT5 target genes imparts both cytokine-independent survival and partial gamma-radiation resistance. These data illustrate both cooperative and redundant effects of STAT5 and Ras signaling in BCR/ABL transformed cells, with STAT5 playing a dominant role in resistance to DNA damage-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Division
  • Cell Survival / drug effects
  • DNA Damage
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / physiology*
  • Genetic Vectors / genetics
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / physiology*
  • Interleukin-3 / pharmacology
  • Milk Proteins*
  • Philadelphia Chromosome
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-pim-1
  • Retroviridae
  • STAT5 Transcription Factor
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / physiology*
  • Transduction, Genetic
  • bcl-X Protein
  • ras Proteins / genetics
  • ras Proteins / physiology*


  • DNA-Binding Proteins
  • Interleukin-3
  • Milk Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • STAT5 Transcription Factor
  • Trans-Activators
  • bcl-X Protein
  • Fusion Proteins, bcr-abl
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-pim-1
  • ras Proteins