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.
Keywords: Acute myeloid leukemia; DZnep; EZH2; MLL; PRC2.
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