Expression of the MOZ-TIF2 oncoprotein in mice represses senescence

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.

The many lives of KATs — detectors, integrators and modulators of the cellular environment

“…In general, translocations involving one or more KATs, such as MOZ-NCOA2, bestow pro-tumorigenic characteristics, including increased self-renewal on progenitor cells 163 . In accordance, the MOZ-NCOA2 fusion protein is able to supress expression of the Cdkn2a locus and thus cellular senescence 164 . A recent screen across a spectrum of different malignancies for changes in copy number variations identified MOZ as one of the most significantly amplified loci across an array of cancers 165 .…”

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

“…HSPC self-renewal and leukemia via CBP/p300 acetylation 40 and MOZ is a HAT that depends on HAT activity to inhibit senescence 41 . For these reasons, we hypothesized that AML-ETO9a and HMGN1 overexpression would cooperate in vivo.…”

Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells

“…51 Moreover, the HAT activity of MOZ-TIF2 fusion protein is crucial for repression of Ink4a and prevention of senescence. 52 These reports suggest that repression of Ink4a is important for stem cell maintenance in MOZ-TIF2-induced AML cells; therefore, deletion of Glis2 was not sufficient to restore the leukemic potential of Ring1A/Bdeleted MOZ-TIF2 cells, possibly because of derepression of Ink4a. Indeed, leukemia-initiating capacity was lost in Ring1A 2/2 ; Ring1B D/D ;Glis2 D/D cells in which expression of p16 Ink4a mRNA was derepressed (supplemental Figure 6E).…”