A major obstacle to curing chronic myeloid leukaemia (CML) is residual disease\ud maintained by tyrosine kinase inhibitor (TKI)-persistent leukemic stem cells (LSCs).\ud These are BCR-ABL1 kinase-independent (1, 2), refractory to apoptosis (3, 4) and\ud serve as a reservoir to drive relapse or TKI-resistance. We demonstrate that\ud Polycomb Repressive Complex 2 (PRC2) is mis-regulated in chronic phase (CP)\ud CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets\ud in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific\ud inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell (HSC)\ud survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone\ud caused significant up-regulation of H3K27me3 targets, and combined treatment\ud further potentiated these effects and resulted in significant loss of LSCs compared to\ud TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings\ud point to a promising epigenetic-based therapeutic strategy to more effectively target\ud LSCs in CML patients receiving TKIs
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