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 validate whether upregulation of p16 is responsible for anti-leukemic effect of EZH2 inhibition, we tested shRNA for p16 (shp16) (Fig.3a). Colony forming capacity of MLL/ENL leukemia cells attenuated by shEZH2 was markedly restored by p16 knockdown (Fig.3b). Furthermore, similar results were obtained using MLL/ENL leukemia mice treated with shp16 and DZNep (Fig.3c). In contrast, overexpression of p16 diminished colony number of MLL/ENL leukemia cells (Fig.3d) and showed decreased leukemia initiating capacity in transplantation assay (Fig.3e). These data support the idea that p16 is one of the main targets of EZH2 inhibition.
Affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.