The m5C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism

  • Cell Rep. 2025 May 27;44(5):115661. doi: 10.1016/j.celrep.2025.115661.
Songyu Li  1 ,  Ya Liu  2 ,  Xiang Wu  2 ,  Minjia Pan  3 ,  Hongxia Zhao  2 ,  Yunguang Hong  4 ,  Qinghua Zhang  5 ,  Shushu Hu  5 ,  Aorong Ouyang  6 ,  Guangru Li  2 ,  Minhui Wu  2 ,  Shanshan Fan  2 ,  Zhirong Jia  2 ,  Shanchao Zhao  3 ,  Guocai Wu  7 ,  Xiangwei Gao  8 ,  Zhigang Yang  1 ,  Zhanghui Chen  9
Affiliations
  • 1. Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang 524000, China; Department of Hematology, Central People's Hospital of Zhanjiang, Zhanjiang 524000, China; Zhanjiang Key Laboratory of Leukemia Pathogenesis and Targeted Therapy Research, Zhanjiang 524000, China.
  • 2. Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang 524000, China.
  • 3. Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 4. Department of Hematology, Central People's Hospital of Zhanjiang, Zhanjiang 524000, China; Zhanjiang Key Laboratory of Leukemia Pathogenesis and Targeted Therapy Research, Zhanjiang 524000, China.
  • 5. Department of Radiation Oncology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
  • 6. Department of Urology, Maoming People's Hospital, Maoming 525000, China.
  • 7. Department of Hematology, Central People's Hospital of Zhanjiang, Zhanjiang 524000, China.
  • 8. Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 9. Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang 524000, China. Electronic address: [email protected].
PMID: 40343793 DOI: 10.1016/j.celrep.2025.115661
Abstract

Acute myeloid leukemia (AML) is one of the most prevalent heterogeneous hematologic malignancies with a complicated etiology. RNA post-transcriptional modifications have been linked to the incidence and progression of AML, while the detailed mechanism remains to be elucidated. In this study, we find that NOP2/Sun domain family member 2 (NSUN2), a methyltransferase of 5-methylcytosine (m5C) RNA methylation, is upregulated in AML and predicts a poor prognosis for patients with AML. Knockdown of NSUN2 in AML cells inhibits proliferation and colony formation and promotes Apoptosis. Depletion of NSUN2 in AML mice reduces the tumor burden and prolongs survival. Mechanistically, NSUN2 promotes the expression of phosphoglycerate dehydrogenase (PHGDH) and serine hydroxymethyltransferase 2 (SHMT2), two key Enzymes in the serine/glycine biosynthesis pathway, by stabilizing the corresponding mRNAs through regulation of m5C modifications. Overall, our findings demonstrate a critical role of NSUN2 in AML development and highlight the therapeutic potential of targeting the NSUN2/m5C axis for the treatment of this Cancer.

Keywords
5-methylcytosine; AML; Acute myeloid leukemia; CP: Cancer; CP: Metabolism; NOP2/Sun RNA methyltransferase 2; NSUN2; m(5)C; serine metabolism.
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