Acquired expression of osteopontin selectively promotes enrichment of leukemia stem cells through AKT/mTOR/PTEN/β-catenin pathways in AML cells

Abstract

AimsAcute myeloid leukemia (AML) initiation and progression have been attributed to subpopulations of self-renewing leukemia stem cells (LSCs), which contribute to progression, recurrence and therapeutic resistance in leukemia. Osteopontin (OPN) plays an important role in promoting survival and drug resistance in LSCs. The aim of this study was to explore OPN roles in modulating curcumin-mediated LSC enrichment and survival in AML cell lines and primary CD34+/CD38− bone-marrow-derived AML cells. Materials and methodsThe growth inhibitory effects of curcumin (CUR) were evaluated by MTT assay in U937 and CD34+ KG-1 AML cell lines as well as primary CD34+/CD38− bone-marrow derived AML cells isolated by MACS technique. The proportion of LSC markers (CD34, CD38 and CD123) were evaluated by flow cytometry. The expression levels of OPN, AKT, mTOR, PTEN, β-catenin and NF-κB were investigated by qRT-PCR. Short interfering RNA (siRNA) against OPN was used in AML cells incubated with or without CUR. Key findingsProportions of CD34+/CD38−/CD123+ and CD34+/CD38+/CD123+ LSCs compartment co-expressing an increased level of OPN could be enriched in AML cell lines and in patient's primary cells by CUR treatment. The expression levels of AKT, mTOR, PTEN, and β-catenin and NF-κB1, were also significantly up-regulated concurrently with OPN in the enriched CD34+ AML cells. SignificanceThe increased in CUR-mediated OPN level is involved in a complex interplay of various signaling pathways resulting in cytoprotection and enrichment of CD34+ LSC compartment in CUR-treated AML cells. AKT/mTOR/PTEN/β-catenin/NF-kB signaling pathways may play roles in modulating OPN-mediated LSC cell survival and enrichment.