The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3

Blood. 2003 Feb 15;101(4):1494-504. doi: 10.1182/blood-2002-04-1045. Epub 2002 Oct 24.


Activating mutations of the protein tyrosine kinase (PTK) FLT3 can be found in approximately 30% of patients with acute myeloid leukemia (AML), thereby representing the most frequent single genetic alteration in AML. These mutations occur in the juxtamembrane (FLT3 length mutations; FLT3-LMs) and the second tyrosine kinase domain of FLT3-TKD and confer interleukin 3 (IL-3)-independent growth to Ba/F3 cells. In the mouse bone marrow transplantation model, FLT3-LMs induce a myeloproliferative syndrome stressing their transforming activity in vivo. In this study, we analyzed the pro-proliferative and antiapoptotic potential of FLT3 in FLT3-LM/TKD-mutation-transformed Ba/F3 cells and AML-derived cell lines. The PTK inhibitor SU5614 has inhibitory activity for FLT3 and selectively induces growth arrest, apoptosis, and cell cycle arrest in Ba/F3 and AML cell lines expressing a constitutively activated FLT3. In addition, the compound reverts the antiapoptotic and pro-proliferative activity of FLT3 ligand (FL) in FL-dependent cells. No cytotoxic activity of SU5614 was found in leukemic cell lines that express a nonactivated FLT3 or no FLT3 protein. At the biochemical level, SU5614 down-regulated the activity of the hyperphosphorylated FLT3 receptor and its downstream targets, signal transducer and activator of (STAT) 3, STAT5, and mitogen-activated protein kinase (MAPK), and the STAT5 target genes BCL-X(L) and p21. Our results show that SU5614 is a PTK inhibitor of FLT3 and has antiproliferative and proapoptotic activity in AML-derived cell lines that endogenously express an activated FLT3 receptor. The selective and potent cytotoxicity of FLT3 PTK inhibitors support a clinical strategy of targeting FLT3 as a new molecular treatment option for patients with FLT3-LM/TKD-mutation(+) AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Blotting, Western
  • Bone Marrow Transplantation
  • Cell Division / drug effects*
  • DNA-Binding Proteins / antagonists & inhibitors
  • Enzyme Inhibitors / pharmacology*
  • Flow Cytometry
  • Gene Expression
  • Green Fluorescent Proteins
  • Humans
  • Indoles / pharmacology*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology*
  • Luminescent Proteins / genetics
  • Mice
  • Milk Proteins*
  • Mitogen-Activated Protein Kinases
  • Mutagenesis
  • Mutation
  • Myeloproliferative Disorders / genetics
  • Polymerase Chain Reaction
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • STAT5 Transcription Factor
  • Trans-Activators / antagonists & inhibitors
  • Transfection
  • Tumor Cells, Cultured
  • fms-Like Tyrosine Kinase 3


  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Indoles
  • Luminescent Proteins
  • Milk Proteins
  • Proto-Oncogene Proteins
  • STAT5 Transcription Factor
  • SU 5614
  • Trans-Activators
  • Green Fluorescent Proteins
  • FLT3 protein, human
  • Flt3 protein, mouse
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3
  • Mitogen-Activated Protein Kinases