Interactions between the PI3K and Raf signaling pathways can result in the transformation of hematopoietic cells

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Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
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J A McCubrey1, J T Lee, L S Steelman

  • 1Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.

Cancer Detection and Prevention
|September 4, 2001
PubMed

Insights

The Raf/MEK/ERK pathway, when activated, can promote oncogenic transformation in hematopoietic cells, especially when combined with anti-apoptotic proteins. This pathway

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • The PI3K/Akt and Raf/MEK/ERK signaling pathways are crucial for cell growth, survival, and gene expression.
  • These pathways transmit signals from cell surface receptors to intracellular targets.
  • Dysregulation of these pathways is implicated in various cancers.

Purpose of the Study:

  • To investigate the roles of PI3K/Akt and Raf/MEK/ERK signaling in abrogating cytokine dependence in hematopoietic cells.
  • To determine the oncogenic potential of activated Raf/MEK/ERK signaling.
  • To explore the interactions between these pathways and anti-apoptotic proteins in cell transformation.

Main Methods:

  • Retroviral expression of activated PI3K, Akt, Raf, and MEK proteins in hematopoietic cell lines (FDC-PI, TF-1, FL5.12).
  • Assessment of cytokine independence and transformation frequency.
  • Tumorigenicity assays in immunocompromised mice.
  • Co-expression studies with anti-apoptotic proteins (Bcl-2, Bcl-XL).

Main Results:

  • Activated PI3K or Akt alone did not efficiently abolish cytokine dependence.
  • Activated Raf and MEK abrogated cytokine dependence in FDC-PI and TF-1 cells, with transformation efficiency varying by specific oncogene.
  • Cytokine-independent cells driven by activated Raf formed tumors in mice, confirming oncogenic effects.
  • Overexpression of Bcl-2 enhanced Raf/MEK/ERK-mediated transformation.
  • Activated Raf genes did not relieve cytokine dependence in FL5.12 cells, but combinations with PI3K or Akt did, further enhanced by Bcl-2/Bcl-XL.

Conclusions:

  • The Raf/MEK/ERK pathway activation can lead to oncogenic transformation of certain hematopoietic cells.
  • Interactions between the Raf/MEK/ERK pathway and PI3K/Akt pathway, along with anti-apoptotic proteins, can overcome cytokine dependence and promote transformation.
  • These findings highlight the complex interplay of signaling pathways in cancer development and suggest potential therapeutic targets.

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