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: Next, we studied whether anti-leukemic effect for MLL fusion leukemia by EZH2 inhibition can be applied to various kinds of leukemia. We exposed several human leukemia cell lines to DZNep. K562, HEL, Kasumi-1 and ME-1 cells, all of which do not harbor MLL fusion genes were not sensitive to low concentration of DZNep while both of MLL leukemia cell lines Mv4-11 and MOLM13 were sensitive to 50 nM of DZNep (Fig.4a). Knockdown of EZH2 led to minimal effect on E2A/HLF transduced BM cells or c-Kit positive BM cells as we previously reported,32 while colony forming capacity of MLL/ENL and Hoxa9/Meis1 transduced cells were strongly suppressed (Fig.4b). Knockdown of p16 rescued colony forming capacity of MLL/ENL or Hoxa9/Meis1 transduced cells by EZH2 inhibition (Fig.4c). Expression levels of p16 were not influenced by knockdown of EZH2 in the BM cells transduced with leukemia fusion genes other than MLL/ENL (Fig. S5). In addition, survival of mice transplanted with leukemia cells induced by TPAE is not prolonged by DZNep administration (Fig.4d), although H3K27 were globally hypomethylated (Fig.4e). These data imply that anti-leukemic effect of EZH2 inhibition through p16 upregulation is specific for MLL fusion leukemia.
Affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.