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Expression of the MOZ-TIF2 oncoprotein in mice represses senescence

Anne Largeot1, Flor Maria Perez-Campo1, Elli Marinopoulou1

  • 1Cancer Research UK Stem Cell Biology Group, CR-UK Manchester Institute, University of Manchester, Manchester, UK.

Experimental Hematology
|February 9, 2016
PubMed

Insights

The MOZ-TIF2 fusion protein, crucial in acute myeloid leukemia, silences the p16(INK4a) gene, blocking cellular senescence and promoting leukemia cell survival. Loss of MOZ HAT activity reactivates senescence.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Hematology

Background:

  • The MOZ-TIF2 translocation is linked to acute myeloid leukemia development.
  • MOZ histone acetyltransferase (HAT) activity is critical for regulating cellular safeguards like senescence.
  • Oncogenic fusion proteins often evade senescence and apoptosis to drive cancer progression.

Purpose of the Study:

  • To investigate if the MOZ-TIF2 fusion protein represses p16(INK4a) transcription and blocks senescence.
  • To determine the role of MOZ HAT activity in the function of the MOZ-TIF2 fusion protein.
  • To explore the impact of MOZ-TIF2 on the balance between apoptosis and senescence in leukemia.

Main Methods:

  • Analysis of CDKN2A locus expression (p16(INK4a) and p19(ARF)) in the presence and absence of MOZ HAT activity.
  • Assessment of senescence induction in hematopoietic progenitors.
  • Evaluation of apoptosis rates in relation to senescence.
  • Studies using the MOZ-TIF2 fusion protein and its HAT-deficient mutant.

Main Results:

  • MOZ-TIF2 silences the CDKN2A locus, inhibiting senescence and enhancing proliferation, creating a pro-leukemic environment.
  • Abolishing MOZ HAT activity in MOZ-TIF2 leads to increased CDKN2A expression and senescence in hematopoietic progenitors.
  • Senescence inhibition by MOZ-TIF2 correlates with increased apoptosis, suggesting a role in the p53-mediated apoptosis-versus-senescence pathway.

Conclusions:

  • The HAT activity of MOZ, retained in the MOZ-TIF2 fusion, is essential for repressing CDKN2A transcription and blocking senescence.
  • This repression of senescence by MOZ-TIF2 is a critical mechanism for leukemic cell survival.
  • MOZ-TIF2 influences the apoptosis-senescence balance, highlighting the importance of its HAT function in leukemia pathogenesis.

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