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

Feng Huang, Yushuai Wang, Xiuxin Zhang, Weiwei Gao, Jingwen Li, Ying Yang, Hongjie Mo, Emily Prince, Yifei Long, Jiacheng Hu, Chuang Jiang, Yalin Kang, Zhenhua Chen, Yueh-Chiang Hu, Chengwu Zeng, Lu Yang, Chun-Wei Chen, Jianjun Chen (), Huilin Huang () and Hengyou Weng ()
Additional contact information
Feng Huang: Guangzhou Medical University
Yushuai Wang: Guangzhou National Laboratory
Xiuxin Zhang: Bioland Laboratory
Weiwei Gao: Guangzhou National Laboratory
Jingwen Li: Guangzhou National Laboratory
Ying Yang: Guangzhou National Laboratory
Hongjie Mo: Guangzhou National Laboratory
Emily Prince: Beckman Research Institute of City of Hope
Yifei Long: Sun Yat-sen University Cancer Center
Jiacheng Hu: Bioland Laboratory
Chuang Jiang: Guangzhou National Laboratory
Yalin Kang: Sun Yat-sen University Cancer Center
Zhenhua Chen: Beckman Research Institute of City of Hope
Yueh-Chiang Hu: Cincinnati Children’s Hospital Medical Center
Chengwu Zeng: The Fifth Affiliated Hospital of Guangzhou Medical University
Lu Yang: Beckman Research Institute of City of Hope
Chun-Wei Chen: Beckman Research Institute of City of Hope
Jianjun Chen: Beckman Research Institute of City of Hope
Huilin Huang: Sun Yat-sen University Cancer Center
Hengyou Weng: Guangzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58966-1

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