Abstract: The MOZ-TIF2 translocation, which fuses monocytic leukemia zinc finger protein (MOZ) histone
acetyltransferase (HAT) with the nuclear co-activator TIF2, is associated with the development
of acute myeloid leukemia. We recently found that in the absence of MOZ HAT
activity, p16INK4a 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 p16INK4a 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 (p16INK4a and p19ARF), 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
the CDKN2A locus transcription and the subsequent block of senescence, a necessary step
for the survival of leukemic cells.
