PTEN is fundamental for elimination of leukemia stem cells mediated by GSK126 targeting EZH2 in chronic myelogenous leukemia

Purpose:Leukemia stem cells (LSCs) are important source of tyrosine kinase inhibitor (TKI) resistance and disease relapse in chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that EZH2 was overexpressed in primary CML CD34+ cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism. Experimental Design：Human primary CML CD34+ cells and retrovirally-BCR-ABL-driven CML mouse model were employed to evaluate the effects of suppression of EZH2 by GSK126 or EZH2 specific shRNA in vitro and in vivo. Recruitment of EZH2 and H3K27me3 on the promoter of tumor suppressor gene PTEN in CML cells was measured by chromatin immunoprecipitation (ChIP) assay. Results: Our results showed that pharmacological inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34+ cells while sparing those from normal bone marrow (NBM) CD34+ cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. EZH2 knockdown resulted in elevation of PTEN and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of PTEN gene. The effect of EZH2 knockdown in the CML mice was at least partially reversed by PTEN knockdown. Conclusions: These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs, and warrants clinical trial of GSK126 in refractory patients with CML.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yNpVlo