METTL3 mediates bone marrow mesenchymal stem cell adipogenesis to promote chemoresistance in acute myeloid leukaemia

• Published in: FEBS open bio Vol. 11; no. 6; pp. 1659 - 1672
• Main Authors: Pan, Zhi‐peng, Wang, Bin, Hou, Di‐yu, You, Ruo‐lan, Wang, Xiao‐ting, Xie, Wen‐hui, Huang, Hui‐fang, Moor, Cornelia H.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2021; John Wiley and Sons Inc; Wiley
• Subjects: Acute myeloid leukemia; Adipocytes; Adipogenesis; Adult; AKT protein; AKT1 protein; AML; Bone marrow; Bone marrow transplantation; Cell Line, Tumor; Chemoresistance; Drug Resistance, Neoplasm; Epigenetics; Female; Gene expression; Humans; Leukemia; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; m6A; Male; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; mesenchymal stromal cells; Methyltransferases - genetics; Methyltransferases - metabolism; Middle Aged; mRNA; MSCs; myeloid leukemia; N6-methyladenosine; protein synthesis; Proteins; RNA modification; Stains & staining; Stem cells; therapeutics; Young Adult; United States > US; China; Germany; AML; m6A; MSCs; chemoresistance; adipogenesis
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13165

Adipogenesis of bone marrow mesenchymal stem cells (MSCs) promotes chemoresistance of acute myeloid leukaemia (AML) cells. MSCs from AML patients (AML‐MSCs) display enhanced adipogenesis compared with bone marrow MSCs from healthy donors. However, the precise molecular mechanism by which adipogenesis of MSCs from AML marrow differs from normal counterparts remains obscure. We found that METTL3 significantly inhibits MSC adipogenesis. Here, we aimed to identify the molecular mechanism linking METTL3 and MSC adipogenesis. Analysis of m6A epigenetic changes in MSCs determined via RIP‐qPCR and MeRIP‐qPCR indicated that METTL3 affects AKT protein expression in MSCs by mediating m6A modification of AKT1‐mRNA. Downregulated METTL3 expression in AML‐MSCs induced an increase in AKT protein, resulting in enhanced MSC adipogenesis, thereby contributing to chemoresistance in AML cells. Therefore, targeting AKT regulation by mRNA modification in MSC adipogenesis might provide a novel therapeutic strategy to overcome AML chemoresistance. We find that METTL3 reduces the level of m6A modification of AKT‐mRNA transcripts, which prevents reader protein‐mediated AKT‐mRNA decay, thereby increasing mRNA stability and protein expression. Activation of the PI3K/AKT pathway promoted adipogenic differentiation of MSCs, thereby contributing to chemoresistance of AML cells. This study provides new insights into AML chemoresistance and may benefit the treatment of AML. ​