Tandem-duplicated Flt3 Constitutively Activates STAT5 and MAP Kinase and Introduces Autonomous Cell Growth in IL-3-dependent Cell Lines

Oncogene. 2000 Feb 3;19(5):624-31. doi: 10.1038/sj.onc.1203354.

Abstract

We have recently identified an internal tandem duplication of the human Flt3 gene in approximately 20% of acute myeloid leukemia (AML) cases. In the present study, the wild-type and the mutant Flt3 genes were transfected into two IL-3-dependent cell lines, 32D and BA/F3 cells. Mutant Flt3-transfected cells exhibited autonomous growth while wild-type Flt3-transfected cells with the continuous stimulation of Flt3 ligand exhibited a minimal proliferation. Cells expressing mutant Flt3 showed constitutive activation of STAT5 and MAP kinase. In contrast, Flt3 ligand stimulation caused rapid activation of MAP kinase but not STAT5 in cells expressing wild-type Flt3. Finally, we found constitutive activation of MAP kinase and STAT5 in all clinical samples of AML patients with mutant Flt3. Our study shows the significance of internal tandem duplication of Flt3 receptors for leukemia cell expansion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Death / drug effects
  • Cell Division / genetics
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Gene Duplication*
  • Growth Inhibitors / pharmacology
  • Humans
  • Interleukin-3 / physiology*
  • Leukemia, Erythroblastic, Acute / pathology
  • MAP Kinase Signaling System / drug effects
  • Milk Proteins*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • Mutation / genetics
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Repetitive Sequences, Amino Acid
  • STAT5 Transcription Factor
  • Trans-Activators / metabolism*
  • Tumor Cells, Cultured
  • fms-Like Tyrosine Kinase 3

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Flavonoids
  • Growth Inhibitors
  • Interleukin-3
  • Milk Proteins
  • Proto-Oncogene Proteins
  • STAT5 Transcription Factor
  • Trans-Activators
  • FLT3 protein, human
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one