NAT10-mediated mRNA N4-acetylcytidine reprograms serine metabolism to drive leukaemogenesis and stemness in acute myeloid leukaemia
RNA modification has emerged as an important epigenetic mechanism that controls abnormal metabolism and growth in acute myeloid leukaemia (AML). However, the roles of RNA N<sup>4</sup>-acetylcytidine (ac4C) modification in AML remain elusive. Here, we report that ac4C and its catalytic enzyme NAT10 drive leukaemogenesis and sustain self-renewal of leukaemic stem cells/leukaemia-initiating cells through reprogramming serine metabolism. Mechanistically, NAT10 facilitates exogenous serine uptake and de novo biosynthesis through ac4C-mediated translation enhancement of the serine transporter SLC1A4 and the transcription regulators HOXA9 and MENIN that activate transcription of serine synthesis pathway genes. We further characterize fludarabine as an inhibitor of NAT10 and demonstrate that pharmacological inhibition of NAT10 targets serine metabolic vulnerability, triggering substantial anti-leukaemia effects both in vitro and in vivo. Collectively, our study demonstrates the functional importance of ac4C and NAT10 in metabolism control and leukaemogenesis, providing insights into the potential of targeting NAT10 for AML therapy.
Authors
- Yaojun Zhang (ORCID: https://orcid.org/0000-0002-9752-4729)
- Yueting Wen
- Shenghua Dong (ORCID: https://orcid.org/0000-0001-8490-8144)
- Yushuai Wang (ORCID: https://orcid.org/0000-0002-2034-3743)
- Huilin Huang (ORCID: https://orcid.org/0000-0003-2608-572X)
- Xiuxin Zhang (ORCID: https://orcid.org/0000-0001-8465-7365)
- H. J. Mo (ORCID: https://orcid.org/0000-0001-5356-2419)
- Feng Huang (ORCID: https://orcid.org/0000-0003-4203-4244)
- Lili Pan (ORCID: https://orcid.org/0000-0001-6326-3260)
- Jiacheng Hu (ORCID: https://orcid.org/0000-0003-3630-5829)
- Yijun Gao (ORCID: https://orcid.org/0000-0003-4978-3205)
- Baiqing Li (ORCID: https://orcid.org/0000-0001-8351-8267)
- Hengyou Weng (ORCID: https://orcid.org/0000-0001-6474-2861)
- Subo Zhang (ORCID: https://orcid.org/0000-0003-0878-5394)
- Zhoutian Yang (ORCID: https://orcid.org/0009-0007-0261-8479)
- Yun Wang (ORCID: https://orcid.org/0000-0002-3296-3421)
- Jianjun Chen (ORCID: https://orcid.org/0000-0003-3749-2902)
- Shilin Zhang (ORCID: https://orcid.org/0000-0001-8430-5095)
- Hongming Chen (ORCID: https://orcid.org/0000-0002-8065-8333)
- Yingmin Li (ORCID: https://orcid.org/0000-0002-1269-173X)
- Liang Yang (ORCID: https://orcid.org/0000-0002-1173-1859)
- Yuanpei Li (ORCID: https://orcid.org/0000-0002-9450-1468)
- Ying Yang (ORCID: https://orcid.org/0000-0002-9258-5098)
- Weiwei Gao (ORCID: https://orcid.org/0000-0003-1901-4595)
- Yifei Long (ORCID: https://orcid.org/0000-0002-8601-183X)
- Yadi Liu (ORCID: https://orcid.org/0000-0002-5706-0966)
- Wenting Liao (ORCID: https://orcid.org/0000-0003-4953-3134)
- Xiao Du
- Yalin Kang
- Yunda Song
- Youmei Xia
Institutions
- University of Science and Technology of China (CN)
- Fujian Medical University (CN)
- Sun Yat-sen University (CN)
- Shantou University (CN)
- First Affiliated Hospital of Guangzhou Medical University (CN)
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN)
- City of Hope (US)
- Shantou University Medical College (CN)
- Sun Yat-sen University Cancer Center (CN)
- State Key Laboratory of Respiratory Disease (CN)
- Union Hospital (CN)
- Beckman Research Institute
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2024-11-06
- DOI
- https://doi.org/10.1038/s41556-024-01548-y
- Citations
- 28
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 6.55
Funders
- Guangzhou Science and Technology Program key projects