Paediatrics (RCH) - Research Publications

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Author: Brumatti, Gabriela × Author: Ekert, Paul × End date: 2019 × Start date: 2010 ×

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    Quantitative proteomic analysis of EZH2 inhibition in acute myeloid leukemia reveals the targets and pathways that precede the induction of cell death
    Sandow, JJ ; Infusini, G ; Holik, AZ ; Brumatti, G ; Averink, TV ; Ekert, PG ; Webb, AI (WILEY-V C H VERLAG GMBH, 2017-09)
    PURPOSE: Chromosomal translocation of the mixed lineage leukemia (MLL) locus generates fusion proteins that drive acute myeloid leukemia (AML) resulting in atypical histone methyltransferase activity and alterations in the epigenetic regulation of gene expression. Targeting histone regulators, such as Enhancer of Zeste Homologue 2 (EZH2), has shown promise in AML. Profiling differential protein expression following inhibition of epigenetic regulators in AML may help to identify novel targets for therapeutics. EXPERIMENTAL DESIGN: Murine models of AML combined with quantitative SILAC analysis were used to identify differentially expressed proteins following inhibition of EZH2 activity using 3-Deazaneplanocin A (DZnep). Western blotting and flow cytometry were used to validate a subset of differentially expressed proteins. Gene set analysis was used to determine changes to reported EZH2 target genes. RESULTS: Our quantitative proteomic analysis and subsequent validation of protein changes identified that epigenetic therapy leads to cell death preceded by the induction of differentiation with concurrent p53 up-regulation and cell cycle arrest. Gene set analysis revealed a specific subset of EZH2 target genes that were regulated by DZnep in AML. CONCLUSION AND CLINICAL RELEVANCE: These discoveries highlight how this new class of drugs affects AML cell biology and cell survival, and may help identify novel targets and strategies to increase treatment efficacy.
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    HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia
    Brumatti, G ; Salmanidis, M ; Kok, CH ; Bilardi, RA ; Sandow, JJ ; Silke, N ; Mason, K ; Visser, J ; Jabbour, AM ; Glaser, SP ; Okamoto, T ; Bouillet, P ; D'Andrea, RJ ; Ekert, PG (IMPACT JOURNALS LLC, 2013-11)
    Deregulated expression of Hox genes such as HoxA9 is associated with development of myeloproliferative disorders and leukemia and indicates a poor prognosis. To investigate the molecular mechanisms by which HoxA9 promotes immortalization of hematopoietic cells, we generated growth factor dependent myeloid cells in which HoxA9 expression is regulated by administration of 4-hydroxy-tamoxifen. Maintenance of HoxA9 overexpression is required for continued cell survival and proliferation, even in the presence of growth factors. We show for the first time that maintenance of Bcl-2 expression is critical for HoxA9-dependent immortalization and influences the latency of HoxA9-dependent leukemia. Hematopoietic cells lacking Bcl-2 were not immortalized by HoxA9 in vitro. Furthermore, deletion of Bcl-2 delayed the onset and reduced the severity of HoxA9/Meis1 and MLL-AF9 leukemias. This is the first description of a molecular link between HoxA9 and the regulation of Bcl-2 family members in acute myeloid leukemia.