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Leukemia stem cells ( LSC ) are resistant to conventional chemotherapy and persistent  LSC  after chemotherapy are supposed to be a major cause of relapse. However, information on genetic or epigenetic regulation of stem cell properties is still limited and  LSC ‐targeted drugs have scarcely been identified. Epigenetic regulators are associated with many cellular processes including maintenance of stem cells. Of note are polycomb group proteins, because they potentially control stemness, and can be pharmacologically targeted by a selective inhibitor ( DZN ep). Therefore, we investigated the therapeutic potential of  EZH 2 inhibition in mixed lineage leukemia ( MLL ) fusion leukemia. Intriguingly,  EZH 2 inhibition by  DZN ep or sh RNA  not only suppressed  MLL  fusion leukemia proliferation but also reduced leukemia initiating cells ( LIC ) frequency. Expression analysis suggested that p16 upregulation was responsible for  LIC s reduction. Knockdown of p16 canceled the survival advantage of mice treated with  DZN ep. Chromatin immunoprecipitation assays demonstrated that  EZH 2 was highly enriched around the transcription‐start‐site of p16, together with  H 3 K 27 methylation marks in  MLL / ENL  and Hoxa9/Meis1 transduced cells but not in  E 2 A / HLF  transduced cells. Although high expression of Hoxa9 in  MLL  fusion leukemia is supposed to be responsible for the recruitment of  EZH 2, our data also suggest that there may be some other mechanisms independent of Hoxa9 activation to suppress p16 expression, because expression levels of Hoxa9 and p16 were not inversely related between  MLL / ENL  and Hoxa9/Meis1 transduced cells. In summary, our findings show that  EZH 2 is a potential therapeutic target of  MLL  fusion leukemia stem cells.

Inhibition of histone methyltransferase EZH 2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16