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BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients

D D De Carvalho1, R Binato, W O Pereira

  • 1Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.

Oncogene
|September 15, 2010
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is downregulated in chronic myeloid leukemia (CML). PRAME and EZH2 regulate TRAIL, and targeting them may improve CML treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Leukemia Research

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cells but is downregulated in cancers like BCR-ABL-positive leukemia.
  • The mechanisms of TRAIL inhibition in tumors are not fully understood, despite its regulation by retinoic acid and the inhibitory role of PRAME/EZH2 in related pathways.
  • TRAIL expression is inversely correlated with BCR-ABL in chronic myeloid leukemia (CML) patients.

Purpose of the Study:

  • To investigate the association between PRAME, EZH2, and TRAIL in BCR-ABL-positive leukemia.
  • To elucidate the regulatory mechanism of TRAIL downregulation in CML.
  • To explore the therapeutic potential of targeting PRAME/EZH2 for CML treatment.

Main Methods:

  • Analysis of PRAME, EZH2, and TRAIL expression in CML patient samples and cell lines.
  • RNA interference to knock down PRAME and EZH2.
  • Chromatin immunoprecipitation to assess EZH2 binding to the TRAIL promoter.
  • Assessment of Imatinib sensitivity following PRAME/EZH2 knockdown.

Main Results:

  • PRAME is upregulated in BCR-ABL cells and positively correlated with BCR-ABL and inversely with TRAIL in CML patients.
  • Knockdown of PRAME or EZH2 using RNA interference restored TRAIL expression in BCR-ABL-positive cells.
  • EZH2 binding to the TRAIL promoter was observed and diminished upon PRAME knockdown.
  • Knockdown of PRAME or EZH2 enhanced TRAIL expression and increased sensitivity to Imatinib.

Conclusions:

  • PRAME, not EZH2, is upregulated in BCR-ABL+ leukemia and inversely correlates with TRAIL expression.
  • A novel regulatory mechanism involving PRAME and EZH2 suppresses TRAIL expression in CML.
  • Targeting PRAME and EZH2 offers a potential therapeutic strategy to restore TRAIL expression and enhance CML treatment efficacy.

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