title: 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, 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 the CDKN2A locus transcription and the subsequent block of senescence, a necessary step for the survival of leukemic cells.
authors: Cancer Research UK Stem Cell Biology Group, CR-UK Manchester Institute, University of Manchester, Manchester, UK.
authors: Anne
authors: A
authors: Largeot
authors: Cancer Research UK Stem Cell Biology Group, CR-UK Manchester Institute, University of Manchester, Manchester, UK. Electronic address: f.perezcampo@unican.es.
authors: Flor Maria
authors: FM
authors: Perez-Campo
authors: Cancer Research UK Stem Cell Biology Group, CR-UK Manchester Institute, University of Manchester, Manchester, UK.
authors: Elli
authors: E
authors: Marinopoulou
authors: Cancer Research UK Stem Cell Biology Group, CR-UK Manchester Institute, University of Manchester, Manchester, UK.
authors: Michael
authors: M
authors: Lie-a-Ling
authors: Cancer Research UK Stem Cell Hematopoiesis Group, CR-UK Manchester Institute, University of Manchester, Manchester, UK.
authors: Valerie
authors: V
authors: Kouskoff
authors: Cancer Research UK Stem Cell Biology Group, CR-UK Manchester Institute, University of Manchester, Manchester, UK. Electronic address: georges.lacaud@cruk.manchester.ac.uk.
authors: Georges
authors: G
authors: Lacaud
mesh_terms: D000818:Animals; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D056426:Genetic Loci; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014161:Transduction, Genetic
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D051958:Nuclear Receptor Coactivator 2; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D051548:Histone Acetyltransferases; C511438:MOZ protein, mouse; D019009:Proto-Oncogene Proteins c-kit