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The role of the PTEN/AKT Pathway in NOTCH1-induced leukemia

Teresa Palomero1, Maria Dominguez, Adolfo A Ferrando

  • 1Institute for Cancer Genetics-Columbia University, New York, New York, USA.

Cell Cycle (Georgetown, Tex.)
|April 17, 2008
PubMed

Insights

Loss of PTEN in T-cell acute lymphoblastic leukemia (T-ALL) causes resistance to NOTCH inhibition. These T-ALL cells become addicted to AKT signaling and are sensitive to AKT inhibitors, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Activating NOTCH1 mutations are common in T-cell acute lymphoblastic leukemia (T-ALL).
  • Gamma-secretase inhibitors (GSIs) targeting NOTCH1 are a proposed therapy, but T-ALL resistance is frequent.
  • PTEN loss is a common event in T-ALL, linked to GSI resistance.

Purpose of the Study:

  • Investigate the mechanisms of T-ALL resistance to NOTCH inhibition.
  • Identify alternative therapeutic targets in PTEN-null T-ALL.
  • Elucidate the role of the PI3K-AKT pathway in T-ALL pathogenesis and treatment resistance.

Main Methods:

  • Gene expression profiling and mutation analysis in T-ALL cell lines.
  • Investigation of the NOTCH1-HES1-PTEN regulatory axis.
  • Utilized Drosophila melanogaster as a model system to study conserved regulatory circuitry.
  • Assessed sensitivity to AKT inhibitors in PTEN-null T-ALL cells.

Main Results:

  • Mutational loss of PTEN is associated with resistance to NOTCH inhibition in T-ALL.
  • NOTCH1 signaling upregulates the PI3K-AKT pathway via HES1, which suppresses PTEN expression.
  • PTEN loss leads to constitutive AKT activation, increased glucose metabolism, and bypasses NOTCH1 dependency for growth.
  • PTEN-null T-ALL cells exhibit oncogene addiction to AKT and are sensitive to AKT inhibitors.

Conclusions:

  • PTEN loss confers resistance to NOTCH inhibition in T-ALL by activating the AKT pathway.
  • AKT signaling becomes the primary oncogenic driver in PTEN-null T-ALL.
  • Targeting AKT offers a promising therapeutic strategy for GSI-resistant T-ALL.

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