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PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity

Nélida Inés Noguera1,2, Maria Liliana Piredda1,2, Riccardo Taulli3

  • 1Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.

Oncotarget
|September 15, 2016
PubMed

Insights

Acute promyelocytic leukemia (APL) involves the PML/RARA protein inhibiting PTEN expression. All-Trans Retinoic Acid (ATRA) reverses this, restoring PTEN levels and aiding myeloid differentiation.

Area of Science:

  • Hematology
  • Molecular Biology
  • Oncology

Background:

  • Acute promyelocytic leukemia (APL) is defined by the PML/RARA fusion protein.
  • PML/RARA acts as a transcriptional repressor, hindering myeloid differentiation.
  • Reduced PTEN oncosuppressor protein levels are observed in APL blasts.

Purpose of the Study:

  • To investigate the role of PTEN in APL pathogenesis.
  • To elucidate the mechanism by which PML/RARA affects PTEN expression.
  • To explore the impact of All-Trans Retinoic Acid (ATRA) on PTEN in APL.

Main Methods:

  • Analysis of PTEN protein levels in APL patient blasts.
  • Assessing the direct inhibitory effect of PML/RARA on PTEN expression.
  • Chromatin immunoprecipitation assays to study promoter activity.
  • Evaluating the effect of ATRA on PTEN transcription and protein localization.

Main Results:

  • APL blasts exhibit significantly lower PTEN levels compared to other AML subtypes and normal bone marrow.
  • PML/RARA directly suppresses PTEN gene expression.
  • ATRA treatment induces active chromatin at the PTEN promoter, facilitating PU.1 binding and PTEN transcription.
  • ATRA promotes PTEN nuclear re-localization and reduces Aurora A kinase expression via PML/RARA degradation.

Conclusions:

  • PTEN is identified as a key target of PML/RARA in APL.
  • Restoration of PTEN expression by ATRA is a crucial mechanism in APL treatment.
  • Targeting PTEN represents a potential therapeutic strategy for APL.
Keywords:
PML-RARAPTENPU.1oncosuppressor

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