2. Academic Validation
  3. Targeting O-GlcNAcylated METTL3 impedes MDS/AML progression via diminishing SRSF1 m6A modification

Targeting O-GlcNAcylated METTL3 impedes MDS/AML progression via diminishing SRSF1 m6A modification

  • Mol Ther. 2025 Sep 5:S1525-0016(25)00716-6. doi: 10.1016/j.ymthe.2025.08.042.
Junjie Gou 1,  Yi Wang 2,  Jingjing Feng 3,  Kaijing Chang 3,  Kexin Wang 3,  Jingjing Bi 3,  Junqi Ge 3,  Chongfu Zhao 3,  Songdi Wu 4,  Zengqi Tan 3,  Feng Guan 5,  Xiang Li 6
Affiliations

Affiliations

  • 1 Xi'an No. 1 Hospital, First Affiliated Hospital of Northwest University, School of Medicine, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology of Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China.
  • 2 Department of Hematology, Provincial People's Hospital, Xi'an, China.
  • 3 Key Laboratory of Resource Biology and Biotechnology of Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China.
  • 4 Xi'an No. 1 Hospital, First Affiliated Hospital of Northwest University, School of Medicine, Xi'an, China.
  • 5 Key Laboratory of Resource Biology and Biotechnology of Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China. Electronic address: guanfeng@nwu.edu.cn.
  • 6 Xi'an No. 1 Hospital, First Affiliated Hospital of Northwest University, School of Medicine, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology of Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China; Institute of Hematology, School of Medicine, Northwest University, Xi'an, China. Electronic address: xiangli@nwu.edu.cn.
PMID: 40914805 DOI: 10.1016/j.ymthe.2025.08.042
Abstract

N6-methyladenosine (m6A) modification, primarily regulated by methyltransferase-like protein 3 (METTL3), plays a pivotal role in RNA metabolism and leukemogenesis. However, the post-translational mechanisms governing METTL3 stability and function remain incompletely understood. Given the widespread occurrence of O-GlcNAcylation on nuclear and cytosolic proteins, we hypothesized that METTL3 might undergo O-GlcNAcylation, thereby influencing its stability and oncogenic function in myeloid malignancies. In this study, we found that METTL3 is O-GlcNAcylated in both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and its expression positively correlates with O-GlcNAcylation levels. Functional assays demonstrated that O-GlcNAcylation enhances METTL3 protein stability and promotes leukemic cell survival. Mechanistically, O-GlcNAcylated METTL3 stabilizes mRNA of serine- and arginine-rich splicing factor 1 (SRSF1), leading to increased expression of the anti-apoptotic protein Mcl-1. This, in turn, suppresses Apoptosis and supports MDS/AML cell viability. Targeting the O-GlcNAcylated form of METTL3 using a competitive peptide significantly inhibited MDS/AML progression in preclinical models. In conclusion, our findings reveal a novel O-GlcNAcylation-dependent mechanism that regulates METTL3 stability and oncogenic activity through the m6A-SRSF1-MCL-1 axis, highlighting a potential therapeutic strategy for MDS and AML.

Keywords

AML; IGF2BP2; MCL-1; MDS; METTL3; O-GlcNAc; SRSF1; gene splicing; m(6)A modification; targeted therapy.

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