Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

Fumihiko Hayakawa, Masayuki Towatari, Hitoshi Kiyoi, Mitsune Tanimoto, Toshio Kitamura, Hidehiko Saito, Tomoki Naoe

Research output: Contribution to journalArticle

426 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)624-631
Number of pages8
JournalOncogene
Volume19
Issue number5
DOIs
Publication statusPublished - Feb 3 2000

Keywords

  • AML
  • Flt3
  • MAP kinase
  • STAT proteins
  • Tandem duplication

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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