Exosome‐Shuttled METTL14 From AML‐Derived Mesenchymal Stem Cells Promotes the Proliferation and Radioresistance in AML Cells by Stabilizing ROCK1 Expression via an m6A‐IGF2BP3‐Dependent Mechanism
Year: 2024
Type: article
Abstract: Acute myelogenous leukemia (AML)-derived mesenchymal stem cells (MSCs) (AML-MSCs) have been identified to play a significant role in AML progression. The functions of MSCs mainly depend on their paracrine action. Here, we investigated whether AML-MSCs functioned in AML cells by transferring METTL14 (Methyltransferase 14) into AML cells via exosomes. Functional analyses were conducted using MTT assay, 5-ethynyl-2-deoxyuridine assay and flow cytometry. qRT-PCR and western blot analyses detected levels of mRNAs and proteins. Exosomes (exo) were isolated from AML-MSCs by ultracentrifugation. The m6A modification profile was determined by methylated RNA immunoprecipitation (MeRIP) assay. The interaction between Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and Rho Kinase 1 (ROCK1) was validated using RIP assay. AML-MSCs incubation promoted the proliferation and radioresistance in AML cells. Moreover, AML-MSCs incubation led to increases in m6A levels and METTL14 levels in AML cells. METTL14 was transferred into AML cells by packaging into exosomes of AML-MSCs. The knockdown of METTL14 in AML-MSCs exosomes could reduce the proliferation and radioresistance in AML cells. Mechanistically, METTL14 induced ROCK1 m6A modification and stabilized its expression by an m6A-IGF2BP3-dependent mechanism. Rescue assay showed that ROCK1 overexpression reversed the inhibitory effects of METTL14 silencing in AML-MSCs exosomes on AML cell proliferation and radioresistance. Exosome-shuttled METTL14 from AML-MSCs promoted proliferation and conferred radioresistance in AML cells by stabilizing ROCK1 expression via an m6A-IGF2BP3-dependent mechanism.
Source: Drug Development Research
DOI: 10.1002/ddr.70025
Authors: Cheng Wang, Rui Song, Jinjin Yuan, Ge Hou, A lan Chu, Yangyang Huang, Chenhu Xiao, Ting Chai, Chen Sun, Zongwen Liu
Institution: Second Affiliated Hospital of Zhengzhou University
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4405555506