Targeting DNMT1 by demethylating agent OR-2100 increases tyrosine kinase inhibitors-sensitivity and depletes leukemic stem cells in chronic myeloid leukemia

ABL1 tyrosine kinase inhibitors (TKIs) dramatically improve the prognosis of chronic myeloid leukemia (CML), but 10–20% of patients achieve suboptimal responses with low TKIs sensitivity. Furthermore, residual leukemic stem cells (LSCs) are involved in the molecular relapse after TKIs discontinuation. Aberrant DNA hypermethylation contributes to low TKIs sensitivity and the persistence of LSCs in CML. DNMT1 is a key regulator of hematopoietic stem cells, suggesting that aberrant DNA hypermethylation targeting DNMT1 represents a potential therapeutic target for CML. We investigated the efficacy of OR-2100 (OR21), the first orally available single-compound prodrug of decitabine. OR21 exhibited anti-tumor effects as a monotherapy, and in combination therapy it increased TKI-induced apoptosis and induction of tumor suppressor genes including PTPN6 encoding SHP-1 in CML cells. OR21 in combination with imatinib significantly suppressed tumor growth in a xenotransplant model. OR21 and combination therapy decreased the abundance of LSCs and inhibited engraftment in a BCR-ABL1–transduced mouse model. These results demonstrate that targeting DNMT1 using OR21 exerts anti-tumor effects and impairs LSCs in CML. Therefore, combination treatment of TKIs and OR21 represents a promising treatment strategy in CML. •The new demethylating agent OR-2100 increased the anti-tumor effect of TKIs.•OR-2100 impaired maintenance of leukemic stem cells in vivo through targeting DNMT1.•OR-2100 combined with TKIs can be promising for treatment of CML.