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Over-expression of Flt3 induces NF-kappaB pathway and increases the expression of IL-6

Shinichiro Takahashi1, Hideo Harigae, Keiko Kumura Ishii

  • 1Department of Clinical Laboratory Medicine, Tohoku University School of Medicine, 1-1 Seiryou-machi, Aobaku, Sendai 980-8574, Japan. shintak@mail.tains.tohoku.ac.jp

Leukemia Research
|June 28, 2005
PubMed

Insights

Activating Fms-like tyrosine kinase 3 (Flt3) mutations in acute myeloblastic leukemia (AML) activate signaling pathways. This study reveals Flt3 signaling upregulates nuclear factor-kappa B (NF-kappaB) and its target IL-6, suggesting Flt3

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Activating mutations or over-expression of Fms-like tyrosine kinase 3 (Flt3) are common in acute myeloblastic leukemia (AML).
  • Flt3 signaling activates Ras/MAP kinase and other pathways crucial in cancer development.
  • Nuclear factor-kappa B (NF-kappaB) is a key transcription factor regulated by these kinase pathways.

Purpose of the Study:

  • To investigate the role of Flt3 in the activation of the NF-kappaB signaling pathway.
  • To determine if Flt3 signaling influences the expression of NF-kappaB target genes, such as Interleukin-6 (IL-6).

Main Methods:

  • Utilized BaF3 cells engineered for stable Flt3 expression.
  • Employed an NF-kappaB-responsive reporter assay to measure pathway activation.
  • Quantified IL-6 mRNA expression in cell lines and primary AML specimens.
  • Analyzed the correlation between Flt3 and IL-6 mRNA levels in AML patient samples.

Main Results:

  • Flt3 expression led to the upregulation of an NF-kappaB-responsive reporter in BaF3 cells.
  • Flt3 signaling, specifically through the Flt3-ERK/MAPK pathway, resulted in increased IL-6 expression.
  • A modest positive correlation (r=0.35, p=0.096) was observed between Flt3 and IL-6 mRNA levels in 24 AML specimens.

Conclusions:

  • Flt3 signaling plays a role in the activation of the NF-kappaB pathway.
  • Flt3 over-expression may contribute to the pathogenesis of AML by upregulating NF-kappaB and IL-6.
  • These findings highlight a potential therapeutic target in Flt3-driven AML.

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