Secreted frizzled-related protein 2 (SFRP2) has been reported to act as a tumor suppressors. This study aims to detect the biological role of SFRP2 in advanced chronic myeloid leukemia (CML). In this study we examined bone marrow samples from 45 CML patients and 10 healthy donors. K562 and KCL22 cells were cultured and treated with demethylation drug and histone deacetylase inhibitor (HDACi). KCL22 and K562 cells were transfected with lentiviral vector (LV)-SFRP2, LV-control. The cells were then subjected to proliferation and apoptosis assays, real time polymerase chain reaction (PCR), Methylationspecific PCR (MSP), Western blotting, co-immunoprecipitation (ColP) and Chromatin immunoprecipitation (ChIP), We found that SFRP2 was down-regulated in the accelerated and blast phase of CML, whereas, the levels of WNTI, WNT3 and WNT5A were up-regulated in the accelerated and blast phase of CML. Overexpression SFRP2 inhibited proliferation, promoted apoptosis and activated the WNT pathway. CoIP-MS results showed that SFRP2 interacted with WNTI and WNT5A. ChIP-seq result indicated that the promoter of H3K4me3 and H3K27me3 were able to interact with SFRP2. In conclusion, our findings demonstrated the SFRP2 act as a potential therapeutic target for advanced CML. Furthermore, our results support the use of demethylation drugs and HDACi as a potential CML treatment strategy. (C) 2018 Elsevier Inc. All rights reserved.