Abstract
Constitutive Stat5 activation enhanced cell survival and resistance to imatinib (IM) in chronic myelogenous leukemia (CML) cells. However, the mechanism of Stat5 activation in mediating resistance to IM in bone marrow (BM) microenvironment has not been evaluated precisely. In this study, we reported HS-5-derived conditioned medium (CM) significantly enhanced IM resistance in K562 and KU812. Interestingly, upregulation of the proportion of CD34+ subpopulation was found in CML cells. Subsequently, the BCR/ABL-independent activation of Stat5 increased P-glycoprotein (P-gp) activity in CM-mediated protection of CML stem cells (LSCs) from IM. Further research revealed Stat5 activation increased the DNA binding activity of NF-κB though binding of p-Stat5 and p-RelA in nucleus. Moreover, highly acetylated RelA was required for Stat5-mediated RelA nuclear binding. The study further confirmed that Wogonin potentiated the inhibitory effects of IM on leukemia development by suppressing Stat5 pathway both in CM model and the K562 xenograft model. In summary, results clearly demonstrated BCR/ABL-independent Stat5 survival pathway could contribute to resistance of CML LSCs to IM in BM microenvironment and suggested that natural durgs effectively inhibiting Stat5 may be an attractive approach to overcome resistance to BCR/ABL kinase inhibitors.
Highlights
IM has proven to be highly effective for inhibiting BCR-ABL tyrosine kinase inhibitors (TKI) in treatment of chronic myelogenous leukemia (CML) [1]
We found that conditioned medium (CM) contributed to BCR/ABLindependent IM resistance by enhancing LSCs survival via activating Stat5/NF-κB signaling
CM induced IM resistance in K562 cells was reported, few research has been undertaken to evaluate the mechanism of resistance in K562 cells subpopulation by CM-derived HS-5
Summary
IM has proven to be highly effective for inhibiting BCR-ABL tyrosine kinase inhibitors (TKI) in treatment of CML [1]. Cessation of drug treatment led to disease relapse in most CML patients [2]. To understand the mechanisms underlying CML persistence, previous studies have mainly focused on cell-intrinsic mechanisms such as BCR/ABL overexpression, Kinase mutations as well as drug influx and efflux regulations [3,4,5]. Recent emerging evidence demonstrated that BM microenvironment provided critical signals to support LSCs preservation in development of drug resistance [6]. There is increasing interest in inhibiting Stat directly to overcome resistance to BCR/ABL kinase inhibitors. The role of Stat signaling pathway in mediating resistance to TKI in the microenvironment has not been sufficient to elucidate
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