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The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia

Maria Francisca Arteaga1, Jan-Henrik Mikesch, Jihui Qiu

  • 1Leukaemia and Stem Cell Biology Group, Department of Haematological Medicine, King's College London, Denmark Hill, London SE5 9NU, UK.

Cancer Cell
|March 23, 2013
PubMed

Insights

Researchers found that the histone demethylase PHF8 is crucial for all-trans retinoic acid (ATRA) effectiveness in acute promyelocytic leukemia (APL). Manipulating PHF8 activity can overcome ATRA resistance in APL patients.

Area of Science:

  • Hematology
  • Molecular Biology
  • Oncology

Background:

  • All-trans retinoic acid (ATRA) is a cornerstone therapy for acute promyelocytic leukemia (APL), targeting oncogenic transcription factors.
  • Mechanisms of ATRA action are not fully understood, and ATRA resistance remains a clinical challenge, leading to patient relapse.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying ATRA response and resistance in APL.
  • To identify novel therapeutic targets for overcoming ATRA resistance in APL.

Main Methods:

  • Investigated the role of histone demethylase PHF8 in ATRA-treated APL cells.
  • Assessed the impact of PHF8 expression and enzymatic activity on ATRA sensitivity.
  • Explored pharmacological manipulation of PHF8 to restore ATRA sensitivity in resistant cells.

Main Results:

  • PHF8 acts as a coactivator, recruited by RARα fusions to enhance target gene expression upon ATRA treatment.
  • Forced PHF8 expression resensitizes ATRA-resistant APL cells; PHF8 downregulation induces resistance.
  • ATRA sensitivity is contingent on PHF8's enzymatic activity and phosphorylation state.

Conclusions:

  • PHF8 is a key mediator of ATRA sensitivity in APL.
  • Pharmacological targeting of PHF8 activity presents a promising strategy to overcome ATRA resistance and improve APL treatment outcomes.

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