International Journal of Hematology

, Volume 76, Issue 5, pp 427–435

Constitutive Activation of C-kit by the Juxtamembrane but Not the Catalytic Domain Mutations Is Inhibited Selectively by Tyrosine Kinase Inhibitors STI571 and AG1296

Authors

  • Shuji Ueda
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
  • Hirokazu Ikeda
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
  • Jun Ishiko
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
  • Itaru Matsumura
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
  • Hirokazu Tanaka
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
  • Hirohiko Shibayama
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
  • Hiroyuki Sugahara
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
  • Emi Takai
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
  • Xian Zhang
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
  • Takashi Machii
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
  • Yuzuru Kanakura
    • Department of Hematology and OncologyOsaka University Graduate School of Medicine
Progress in hematology

DOI: 10.1007/BF02982808

Cite this article as:
Ueda, S., Ikeda, H., Mizuki, M. et al. Int J Hematol (2002) 76: 427. doi:10.1007/BF02982808

Abstract

The c-kit receptor tyrosine kinase (KIT) is constitutively activated by 2 types of naturally occurring mutations, the Val559→Gly (G559) mutation in the juxtamembrane domain and the Asp814→Val (V814) mutation in the catalytic domain. We evaluated the effects of the tyrosine kinase inhibitors STI571 and AG1296 on BaF3 cells expressing wild-type KIT (KITWT) or activating mutants of KIT (KITG559 and KITV814) in the presence or absence of the KIT ligand, stem cell factor (SCF). Both STI571 and AG1296 inhibited SCF-dependent activation of KITWT and SCF-independent activation of KITG559 more efficiently, whereas SCF-independent activation of KITV814 was scarcely affected. Furthermore, both inhibitors inhibited SCF-dependent growth of BaF3-KITWT cells and, with higher potencies, SCF-independent growth of BaF3-KITG559 cells through the induction of apoptosis. In contrast, the inhibitors had little or no effect on SCF-independent growth of BaF3-KITV814 cells or on IL-3-dependent growth of BaF3-Mock cells. These results suggested that both inhibitors may be effective therapeutic agents for oncogenic KIT with the juxtamembrane domain mutation, but not with the catalytic domain mutation, and that the activation mechanism of the catalytic domain mutant KIT is complex and entirely different from that of the wild-type KIT or the juxtamembrane domain mutant KIT.Int J Hematol. 2002; 76: 427-435.

Key words

KIT Activating mutation Juxtamembrane domain Catalytic domain Tyrosine kinase inhibitor

Copyright information

© The Japanese Society of Hematology 2002