The Effects of METTL3-Mediated Regulations of the Adipogenic Differentiations of Bone Marrow MSCs Targeting PI3K/AKT Pathways on the Chemo-Resistance of AML

Abstract

Background: The adipogenic differentiations of bone marrow mesenchymal stem cells (MSCs) result in the promotion of the chemo-resistance of AML cells. When compared with bone marrow MSCs from healthy donors (HD-MSCs), it has been observed that the MSCs from AML (AML-MSCs) displayed enhanced adipogenic differentiation abilities. However, the underlying mechanism remains elusive. METTL3-mediated modifications of m6A mRNA play key roles in the regulation of stem cell differentiation. Unfortunately, there has been no research to date which has reported the fact that the increases of adipogenic differentiation of AML-MSCs are regulated by the m6A. The goal of this study was to investigate the critical role of METTL3 in the adipogenesis of AML-MSCs for promoting the chemo-resistance of AML.Methods: This study detected the m6A levels of the MSCs total RNA, and then investigated METTL3 functions in the adipogenic differentiations of MSCs using knockdown and overexpression experimental methods. The effects of the adipogenic differentiations of HD-MSCs/AML-MSCs on the chemo-resistance to AML were also examined. In addition, the gene transcriptome and m6A epigenetic changes of AML-MSCs from four AML patients, and the HD-MSCs from three healthy donors, were analyzed in this study. The differentially expressed genes and pathways were successfully identified, and clinical specimens were used to adjust gene expressions in order to determine their effects on the adipogenic differentiations of MSC.Results: The results demonstrated that METTL3 could significantly inhibit the adipogenic differentiations of MSCs. It was found that when compared with the HD-MSCs, the expressions of the PI3K/AKT signaling pathways in the AML-MSCs were significantly increased. Meanwhile, the levels of m6A were significantly decreased. Therefore, it was indicated that by blocking the PI3K/AKT signaling pathways with AKT inhibitors, the adipogenic differentiations of the MSCs could be significantly inhibited. Moreover, the increased adipogenic differentiations induced by the METTL3 could significantly increase the chemo-resistance of the AML.Conclusions: It was found that the METTL3 had enhanced the modification levels of m6A in the PI3K/AKT signaling pathways, and then reduced its expression. Subsequently, the adipogenic differentiations were inhibited. Then, the bone marrow microenvironments, as well as chemo-resistance of the AML, were successfully changed.