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

Largeot A, Perez-Campo FM, Marinopoulou E, Lie-A-Ling M, Kouskoff V, Lacaud G.

The MOZ-TIF2 translocation, that fuses MOZ (Monocytic Leukemia Zinc finger protein) histone acetyltransferase (HAT) with the nuclear co-activator TIF2, is associated the development of Acute Myeloid Leukemia. We recently showed that in the absence of MOZ HAT activity, p16INK4atranscriptional levels are significantly increased, triggering an early entrance into replicative senescence. Since oncogenic fusion proteins must bypass cellular safeguard mechanisms, such as senescence or apoptosis in order to induce leukemia, we hypothesized that this repressive activity of MOZ over p16INK4a transcription could be preserved, or even reinforced, in MOZ leukemogenic fusion proteins, such as MOZ-TIF2. We demonstrate here that, indeed, MOZ-TIF2 silences the expression of the CDKN2A locus (p16INK4a and p19ARF), inhibits the triggering of senescence and enhances proliferation, providing conditions favourable to the development of leukemia. Furthermore, we show that abolishing the MOZ HAT activity of the fusion protein leads to a significant increase in the expression of the CDKN2A locus and the number of hematopoietic progenitors undergoing senescence. Finally, we demonstrate that inhibition of senescence by MOZ-TIF2 is associated with increased apoptosis, suggesting a role of 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 the repression of the CDKN2A locus transcription and the subsequent block of senescence, a necessary step for the survival of leukemic cells.


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February, 2016


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