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Co-resistance to retinoic acid and TRAIL by insertion mutagenesis into RAM

W Yin1, A Rossin, J L Clifford

  • 1Department of Cell Biology and Signal Transduction, Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC/CNRS/INSERM/ULP, Illkirch Cedex, C U de Strasbourg, France.

Oncogene
|February 2, 2006
PubMed

Insights

Retinoic acid induces leukemia cell death by activating TNF-related apoptosis-inducing ligand (TRAIL) signaling. A novel gene, RAM (retinoic acid modulator), was identified as a key regulator of this process and myeloid differentiation.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • Retinoic acid (RA) is a key therapy for acute promyelocytic leukemia (APL).
  • RA's efficacy involves inducing blast differentiation and activating tumor-selective TNF-related apoptosis-inducing ligand (TRAIL) signaling.
  • Understanding RA downstream mediators is crucial for APL treatment optimization.

Purpose of the Study:

  • To identify novel downstream mediators of retinoic acid (RA) signaling in leukemia cells.
  • To investigate the role of these mediators in RA-induced apoptosis and differentiation.
  • To characterize a novel RA-regulated gene, RAM (retinoic acid modulator).

Main Methods:

  • Retrovirus-mediated insertion mutagenesis in PLB985 leukemia cells to generate an RA-resistant cell line (WY-1).
  • RNA interference (RNAi) for gene knockdown (TRAIL, RAM).
  • Analysis of RA-induced apoptosis, differentiation, G1 arrest, and TRAIL pathway activation (TRAIL, DR4, DR5).

Main Results:

  • RA induced TRAIL and its receptors (DR4, DR5) in PLB985 cells, but not in RA-resistant WY-1 cells.
  • Knockdown of TRAIL blocked RA-induced apoptosis; WY-1 cells showed co-resistance to RA and TRAIL.
  • A novel RA-regulated gene, RAM (retinoic acid modulator), was identified in WY-1 cells; its knockdown promoted RA-induced differentiation and TRAIL-triggered apoptosis.

Conclusions:

  • RA induces apoptosis in leukemia cells via the TRAIL pathway, independent of the RARalpha oncofusion protein.
  • RAM (retinoic acid modulator) acts as a novel negative regulator of RA-induced myeloid differentiation and apoptosis.
  • RAM RNA may have functions beyond protein coding, influencing RA signaling pathways.

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