2. Academic Validation
  3. m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability

m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability

  • Nat Commun. 2025 May 6;16(1):4214. doi: 10.1038/s41467-025-58966-1.
Feng Huang # 1 2 3,  Yushuai Wang # 2,  Xiuxin Zhang # 3 4,  Weiwei Gao # 2 5,  Jingwen Li 2 3,  Ying Yang 2 3,  Hongjie Mo 2 3,  Emily Prince 6,  Yifei Long 7,  Jiacheng Hu 3 4,  Chuang Jiang 2 3,  Yalin Kang 7,  Zhenhua Chen 6,  Yueh-Chiang Hu 8,  Chengwu Zeng 9 10,  Lu Yang 6,  Chun-Wei Chen 6,  Jianjun Chen 11 12,  Huilin Huang 13,  Hengyou Weng 14 15 16
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China.
  • 2 Guangzhou National Laboratory, Guangzhou, China.
  • 3 Bioland Laboratory, Guangzhou, China.
  • 4 Shantou University Medical College, Shantou, China.
  • 5 University of Science and Technology of China, Hefei, China.
  • 6 Department of Systems Biology and Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
  • 7 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 8 Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 9 Department of Hematology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China.
  • 10 Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, 510632, China.
  • 11 Department of Systems Biology and Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA. jianchen@coh.org.
  • 12 The Gehr Family Center for Leukemia Research, Beckman Research Institute of City of Hope, Monrovia, CA, USA. jianchen@coh.org.
  • 13 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.
  • 14 The First Affiliated Hospital, The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China. weng_hengyou@gzlab.ac.cn.
  • 15 Guangzhou National Laboratory, Guangzhou, China. weng_hengyou@gzlab.ac.cn.
  • 16 Bioland Laboratory, Guangzhou, China. weng_hengyou@gzlab.ac.cn.
  • # Contributed equally.
PMID: 40328743 DOI: 10.1038/s41467-025-58966-1
Abstract

Metabolic reprogramming of Amino acids represents a vulnerability in Cancer cells, yet the mechanisms underlying serine metabolism in acute myeloid leukemia (AML) and leukemia stem/initiating cells (LSCs/LICs) remain unclear. Here, we identify RNA N6-methyladenosine (m6A) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of m6A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies m6A on mRNAs of key serine synthesis pathway (SSP) genes (e.g., ATF4, PHGDH, PSAT1), stabilizing these transcripts and sustaining serine production to meet the high metabolic demand of AML cells and LSCs/LICs. IGF2BP3 silencing combined with dietary SG restriction potently inhibits AML in vitro and in vivo, while its deletion spares normal hematopoiesis. Our findings reveal the critical role of m6A modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/m6A/SSP axis as a promising therapeutic target.

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