High TRAIL-R3 expression on leukemic blasts is associated with poor outcome and induces apoptosis-resistance which

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M E D Chamuleau1, G J Ossenkoppele, A van Rhenen

  • 1Department of Haematology, VU University Medical Centre, Amsterdam, The Netherlands. m.chamuleau@vumc.nl

Leukemia Research
|February 2, 2011
PubMed

Insights

Acute myeloid leukemia (AML) cells express TRAIL receptors, but decoy receptor TRAIL-R3 limits apoptosis. Targeting TRAIL-R2 with antibodies offers a new therapeutic strategy for AML patients.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • The TNF-related apoptosis-inducing ligand (TRAIL) pathway induces apoptosis in cancer cells via specific receptors.
  • TRAIL receptors include pro-apoptotic (TRAIL-R1, TRAIL-R2) and decoy (TRAIL-R3, TRAIL-R4) types.
  • Decoy receptors can inhibit TRAIL-mediated apoptosis.

Purpose of the Study:

  • To investigate TRAIL receptor expression in acute myeloid leukemia (AML) blasts.
  • To determine the correlation between TRAIL receptor expression and patient survival.
  • To evaluate the therapeutic potential of targeting TRAIL receptors in AML.

Main Methods:

  • Flow-cytometric analysis of TRAIL receptor expression on AML blasts and normal cells.
  • Correlation analysis between receptor expression and overall survival.
  • Assessment of cell death induction by soluble TRAIL and anti-TRAIL-R2 antibodies.
  • Evaluation of TRAIL-R3 down-modulation effects.

Main Results:

  • AML blasts express higher levels of pro-apoptotic TRAIL receptors compared to normal blasts.
  • High expression of decoy receptor TRAIL-R3 in AML patients correlates with shortened overall survival.
  • TRAIL-R3 is highly expressed on leukemia-initiating stem cells (CD34+/CD38-).
  • Targeting TRAIL-R2 with antibodies significantly enhanced cancer cell death (up to 80%).

Conclusions:

  • Co-expression of TRAIL-R3 on AML blasts contributes to poor prognosis.
  • TRAIL-R3 acts as a functional decoy receptor in AML.
  • Anti-TRAIL-R2 antibodies represent a promising therapeutic strategy for AML.

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