Mesenchymal Stromal Cell-Derived S100A8 Promotes Acute Myeloid Leukemia Progression Via ROS Signaling

Abstract

Introduction: Mesenchymal stromal cell (MSC) is an important cell component in the bone marrow microenvironment. MSC-derived inflammatory factors regulate the progression of acute myeloid leukemia(AML) by regulating the signaling pathways in hematopoietic cells. S100A8 is an inflammatory factor which belong to the calcium-binding protein S100 family. In vivo animals experiments showed that increased expression of S100A8 in MSC was accompanied by increased proliferative MSCs, and decreased mature osteoblasts. MSC-derived S100A8 can also cause mitochondrial dysfunction in hematopoietic stem progenitor cells, induce oxidative stress response and DNA damage repair, that promotes the progression of myeloid dysplastic syndromes (MDS). However, whether MSC-derived S100A8 involved in AML development have not been reported. In this study, we attempted to elucidate the regulation of MSC-derived S100A8 on MSC itself as well as leukemia cells.Methods: Human MSCs were isolated from AML patients samples by whole bone marrow adherent culture, and the third to fifth passage cells were collected for analysis. The lentivirus vector carrying cDNA of S100A8 gene and the empty lentivirus vector were constructed and infected into MSCs,respectively. Cell cycle and apoptosis of MSCs were analysed by flow cytometry. Acute myeloid leukemia cell line Kasumi-1 was co-cultured with the two groups of mesenchymal stem cells in vitro for 3 days, respectively.cell cycle and apoptosis were analysed, and the cell proliferation was detected by Edu. The ROS levels of co-cultured Kasumi-1 cells were detected by flow cytometry. The apoptosis of kasumi-1 co-cultured cells treated with VP-16 for 48 hour was detected by flow cytometry.Results: The rate of G0 phase cell in S100A8-overexpressed MSCs was higher than in control group.The proliferation rate of Kasumi-1 cells was significantly increased S100A8 overexpressed group than in control after 72-h co-culture, while the apoptosis rate of Kasumi-1 cells was significantly decreased in S100A8 overexpressed group. Futhermore, the apoptosis rate of Kasumi-1 cells co-cultured with S100A8-overexpressed MSCs was markedly lower than in control group after exposed in vp-16 for 48 hour.The ROS level of Kasumi-1 cells co-cultured with S100A8-overexpressed MSCs were significantly increased than those of the control group.Conclusion: S100A8 derived from MSCs plays a critical role in progression and drug resistance of acute myeloid leukemia, by increasing the ROS levels of AML cells, that indicates S100A8 may serve as a potential novel therapeutic target in AML. DisclosuresNo relevant conflicts of interest to declare.