2. Academic Validation
  3. NAT10-mediated mRNA N4-acetylcytidine reprograms serine metabolism to drive leukaemogenesis and stemness in acute myeloid leukaemia

NAT10-mediated mRNA N4-acetylcytidine reprograms serine metabolism to drive leukaemogenesis and stemness in acute myeloid leukaemia

  • Nat Cell Biol. 2024 Dec;26(12):2168-2182. doi: 10.1038/s41556-024-01548-y.
Subo Zhang # 1,  Feng Huang # 2 3,  Yushuai Wang # 2,  Yifei Long # 1,  Yuanpei Li 1,  Yalin Kang 1,  Weiwei Gao 2 4,  Xiuxin Zhang 3 5,  Yueting Wen 2,  Yun Wang 1,  Lili Pan 6 7,  Youmei Xia 1,  Zhoutian Yang 1,  Ying Yang 2 3,  Hongjie Mo 2 3,  Baiqing Li 2 3,  Jiacheng Hu 3 5,  Yunda Song 1,  Shilin Zhang 2,  Shenghua Dong 1,  Xiao Du 1,  Yingmin Li 1,  Yadi Liu 1,  Wenting Liao 1,  Yijun Gao 1,  Yaojun Zhang 1,  Hongming Chen 2 3,  Yang Liang 1,  Jianjun Chen 8,  Hengyou Weng 9 10,  Huilin Huang 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2 Guangzhou National Laboratory, The First Affiliated Hospital, The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China.
  • 3 Bioland Laboratory, Guangzhou, China.
  • 4 Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 5 Shantou University Medical College, Shantou, China.
  • 6 Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
  • 7 Union Clinical Medical Colleges, Fujian Medical University, Fuzhou, China.
  • 8 Department of Systems Biology & Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
  • 9 Guangzhou National Laboratory, The First Affiliated Hospital, The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China. weng_hengyou@gzlab.ac.cn.
  • 10 Bioland Laboratory, Guangzhou, China. weng_hengyou@gzlab.ac.cn.
  • 11 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. huanghl1@sysucc.org.cn.
  • # Contributed equally.
PMID: 39506072 DOI: 10.1038/s41556-024-01548-y
Abstract

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 N4-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.

Figures
Products