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    Expression of the MOZ-TIF2 oncoprotein in mice represses senescence.

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    Authors
    Largeot, Anne
    Perez-Campo, Flor-Maria
    Marinopoulou, Elli
    Lie-A-Ling, Michael
    Kouskoff, Valerie
    Lacaud, Georges
    Affiliation
    Cancer Research UK Stem Cell Biology Group, CR-UK Manchester Institute, The University of Manchester, Wilmslow road, Manchester
    Issue Date
    2016-02-05
    
    Metadata
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    Abstract
    The MOZ-TIF2 translocation, which fuses monocytic leukemia zinc finger protein (MOZ) histone acetyltransferase (HAT) with the nuclear co-activator TIF2, is associated the development of acute myeloid leukemia. We recently found that in the absence of MOZ HAT activity, p16(INK4a) transcriptional levels are significantly increased, triggering an early entrance into replicative senescence. Because oncogenic fusion proteins must bypass cellular safeguard mechanisms, such as senescence and apoptosis, to induce leukemia, we hypothesized that this repressive activity of MOZ over p16(INK4a) transcription could be preserved, or even reinforced, in MOZ leukemogenic fusion proteins, such as MOZ-TIF2. We describe here that, indeed, MOZ-TIF2 silences expression of the CDKN2A locus (p16(INK4a) and p19(ARF)), inhibits the triggering of senescence, and enhances proliferation, providing conditions favorable to the development of leukemia. Furthermore, we describe that abolishing the MOZ HAT activity of the fusion protein leads to a significant increase in expression of the CDKN2A locus and the number of hematopoietic progenitors undergoing senescence. Finally, we report that inhibition of senescence by MOZ-TIF2 is associated with increased apoptosis, suggesting a role for the fusion protein in p53 apoptosis-versus-senescence balance. Our results underscore the importance of the HAT activity of MOZ, preserved in the fusion protein, for repression of CDKN2A locus transcription and the subsequent block of senescence, a necessary step for the survival of leukemic cells.
    Citation
    Expression of the MOZ-TIF2 oncoprotein in mice represses senescence. 2016: Exp. Hematol
    Journal
    Experimental Hematology
    URI
    http://hdl.handle.net/10541/600547
    DOI
    10.1016/j.exphem.2015.12.006
    PubMed ID
    26854485
    Type
    Article
    Language
    en
    ISSN
    1873-2399
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.exphem.2015.12.006
    Scopus Count
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