t(8;21) acute myeloid leukaemia cells are dependent on vascular endothelial growth factor (VEGF)/VEGF receptor type2 pathway and phosphorylation of Akt

Br J Haematol. 2006 Dec;135(5):673-82. doi: 10.1111/j.1365-2141.2006.06372.x.

Abstract

Several anti-angiogenic drugs have recently been clinically tested for haematological malignancies. To improve the efficacy of molecular target therapy against angiogenic molecules in acute myeloid leukaemia (AML), we examined the dependency of AML cells on the vascular endothelial growth factor (VEGF)/VEGF receptor type2 (VEGFR2) system by using VEGFR2 kinase inhibitor. Nineteen patient AML samples were cultured with or without VEGFR2 kinase inhibitor. All four t(8;21) viable AML cells showed significant reductions when treated with VEGFR2 kinase inhibitor, although VEGFR2 kinase inhibitor did not affect the cell proliferation of five t(15;17) AML samples. Other AML cases showed variable responses. VEGFR2 kinase inhibitor greatly suppressed the growth of Kasumi-1, a t(8;21) cell line in a dose-dependent manner through induction of apoptosis, but did not show any significant influence on NB4, a t(15;17) cell line. In addition, VEGFR2 kinase inhibitor potentiated the growth inhibitory effect of cytarabine in Kasumi-1. Finally, it was shown that the Akt phosphorylation was augmented by VEGF(165) in Kasumi-1, which was abrogated by VEGFR2 kinase inhibitor. NB4 showed undetectable Akt phosphorylation even with VEGF(165). These data demonstrated that t(8;21) AML cells are dependent on VEGF through VEGFR2, resulting in the phosphorylation of Akt.

Publication types

  • Comparative Study

MeSH terms

  • Acute Disease
  • Adult
  • Aged
  • Blotting, Western / methods
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromosomes, Human, Pair 15
  • Chromosomes, Human, Pair 17
  • Chromosomes, Human, Pair 21*
  • Chromosomes, Human, Pair 8*
  • Female
  • Humans
  • Indoles / therapeutic use*
  • Leukemia, Myeloid / drug therapy
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / metabolism*
  • Male
  • Middle Aged
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrroles / therapeutic use*
  • Translocation, Genetic*
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • 3-((2,4-dimethyl-3-(ethoxycarbonyl)pyrrol-5-yl)methylidenyl)indolin-2-one
  • Indoles
  • Pyrroles
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2
  • Proto-Oncogene Proteins c-akt