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Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors

Maria Teresa Esposito1, Lu Zhao1, Tsz Kan Fung1

  • 1Leukemia and Stem Cell Biology Group, Department of Haematological Medicine, Division of Cancer Studies, King's College London, London, UK.

Nature Medicine
|November 24, 2015
PubMed

Insights

Acute myeloid leukemia (AML) treatments may be improved by targeting poly (ADP-ribose) polymerase (PARP) inhibitors. This approach exploits synthetic lethality in certain AML subtypes by targeting DNA-damage response pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Acute myeloid leukemia (AML) is often driven by transcription factors, which are difficult to target with small molecules.
  • Repressive transcription factors in AML present a unique therapeutic vulnerability.

Purpose of the Study:

  • To investigate the sensitivity of different AML subtypes to poly (ADP-ribose) polymerase (PARP) inhibitors.
  • To elucidate the molecular mechanisms underlying PARP inhibitor (PARPi) sensitivity and resistance in AML.

Main Methods:

  • Assessing the DNA-damage response (DDR) and homologous recombination (HR) gene expression in AML cells.
  • Utilizing genetic and pharmacological inhibition/overexpression of HOXA9.
  • Evaluating the effects of PARP inhibition on AML cell lines with different oncogenic drivers.

Main Results:

  • AMLs driven by repressive transcription factors (AML1-ETO, PML-RARα) are sensitive to PARPi due to compromised DDR.
  • AMLs driven by MLL fusions are DDR-proficient and PARPi-insensitive.
  • Inhibition of MLL downstream target HOXA9 sensitizes MLL leukemia to PARPi, while HOXA9 overexpression confers PARPi resistance to other AML subtypes.

Conclusions:

  • PARP inhibitors show potential for treating specific AML subtypes through synthetic lethality.
  • HOXA9 acts as a key regulator of PARPi sensitivity in AML by modulating DDR and HR gene expression.

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