IL ‐6 Upregulates CD73 in Human Placental Mesenchymal Stem Cells to Promote ATRA ‐Induced NB4 Cell Differentiation in Acute Promyelocytic Leukemia

PURPOSE: To investigate the expression profile of IL-6 in patients with acute promyelocytic leukemia (APL) and its role in modulating the ability of hPMSCs to regulate the differentiation of NB4 cells. METHODS: Peripheral blood samples were obtained from newly diagnosed APL patients and healthy controls. IL-6 levels were measured using flow cytometry-based (FCM) multiplex immunoassays. A co-culture system of hPMSCs and NB4 cells was established. The effects of hPMSCs on ATRA-induced differentiation, proliferation, and phagocytic activity of NB4 cells were evaluated by Wright-Giemsa staining, FCM, CCK-8 assays, and phagocytosis assays. Western blot analysis was performed to investigate the signaling mechanisms by which IL-6 regulates CD73 expression in hPMSCs. To determine whether the regulatory effects of hPMSCs are mediated by CD73, interventions using a CD73 inhibitor and CD73-knockdown hPMSCs were conducted. RESULTS: IL-6 levels were significantly elevated in the peripheral blood of APL patients and showed a positive correlation with both risk stratification and the severity of retinoic acid syndrome (RAS). hPMSCs enhanced ATRA-induced differentiation of NB4 cells while suppressing their proliferation and phagocytic function. Moreover, inhibition or knockdown of CD73 markedly attenuated the pro-differentiation effect of hPMSCs on NB4 cells. NB4 cells exhibited high surface expression of adenosine receptors. IL-6 was found to upregulate CD73 expression in hPMSCs through activation of the PI3K/AKT signaling pathway. CONCLUSIONS: IL-6 enhances the pro-differentiation capacity of hPMSCs toward NB4 cells by upregulating CD73 expression, offering a potential new strategy for the clinical treatment of APL.