Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16.
Bottom Line: Epigenetic regulators are associated with many cellular processes including maintenance of stem cells.Expression analysis suggested that p16 upregulation was responsible for LICs reduction.Knockdown of p16 canceled the survival advantage of mice treated with DZNep.
Affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.Show MeSH
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Mentions: To confirm whether the effect of DZNep against MLL related leukemia is due to EZH2 inhibition, we transduced shRNAs for EZH2 (shEZH2) into MLL/ENL leukemic cells (Fig.2a). The transduced cells were FACS sorted and transplanted to sublethally irradiated mice. Knockdown of EZH2 prolonged the survival of MLL/ENL leukemic mice (Fig.2b). The BM cells transduced with shEZH2 were globally hypomethylated (Fig.2c), and had diminished colony forming capacity with elevated p16 expression (Fig.2d,e). The ratios of L-GMP in mice transplanted with shEZH2 transduced cells were markedly reduced (Fig. S4). These data indicate that therapeutic efficacy of DZNep is due to EZH2 inhibition.
Affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.