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Therapy-resistant acute lymphoblastic leukemia (ALL) cells inactivate FOXO3 to escape apoptosis induction by TRAIL

Michael J Ausserlechner1, Christina Salvador, Andrea Deutschmann

  • 1Department of Pediatrics I, Medical University Innsbruck, Austria.

Oncotarget
|July 6, 2013
PubMed

Insights

Forkhead transcription factors (FOXO) inactivation is linked to prednisone resistance in T-acute lymphoblastic leukemia (T-ALL). Activating FOXO3 triggers apoptosis in T-ALL cells, offering a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Forkhead transcription factors (FOXO) are key regulators of cell fate, influenced by the PI3K-PKB pathway.
  • FOXO inactivation, indicated by cytoplasmic localization, is observed in prednisone-resistant T-acute lymphoblastic leukemia (T-ALL).
  • This suggests a role for FOXO in leukemia development and drug resistance.

Purpose of the Study:

  • To investigate the functional impact of FOXO3 in T-ALL.
  • To elucidate the mechanisms by which FOXO3 induces apoptosis in T-ALL cells.
  • To explore the therapeutic potential of FOXO3 activation in T-ALL.

Main Methods:

  • Utilized a tamoxifen-inducible, phosphorylation-independent FOXO3(A3)ERtm allele for FOXO3 activation in T-ALL cells.
  • Assessed apoptosis induction, death ligand (TRAIL) and BH3-only protein (Noxa) expression.
  • Employed genetic manipulations including knockdown of TRAIL and Noxa, and expression of dominant-negative FADD (dnFADD), CrmA, and dnBID.

Main Results:

  • FOXO3 activation induced caspase-dependent apoptosis in T-ALL cells.
  • FOXO3 upregulated TRAIL and Noxa, activating extrinsic and intrinsic apoptosis pathways.
  • A caspase-8 amplifying feedback loop downstream of FADD was identified, and mitochondrial destabilization was shown to amplify TRAIL signaling.

Conclusions:

  • FOXO3 activation triggers apoptosis in T-ALL cells via both extrinsic and intrinsic pathways, involving TRAIL, Noxa, and caspase-8.
  • Re-expression of p16INK4A represses FOXO3 levels and sensitizes cells to apoptosis, reducing PI3K-PKB dependency.
  • FOXO3 inactivation is crucial for leukemia cell survival, highlighting its potential as a therapeutic target in T-ALL.

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