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

Author

Listed:
  • Feng Huang

    (Guangzhou Medical University
    Guangzhou National Laboratory
    Bioland Laboratory)

  • Yushuai Wang

    (Guangzhou National Laboratory)

  • Xiuxin Zhang

    (Bioland Laboratory
    Shantou University Medical College)

  • Weiwei Gao

    (Guangzhou National Laboratory
    University of Science and Technology of China)

  • Jingwen Li

    (Guangzhou National Laboratory
    Bioland Laboratory)

  • Ying Yang

    (Guangzhou National Laboratory
    Bioland Laboratory)

  • Hongjie Mo

    (Guangzhou National Laboratory
    Bioland Laboratory)

  • Emily Prince

    (Beckman Research Institute of City of Hope)

  • Yifei Long

    (Sun Yat-sen University Cancer Center)

  • Jiacheng Hu

    (Bioland Laboratory
    Shantou University Medical College)

  • Chuang Jiang

    (Guangzhou National Laboratory
    Bioland 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
    School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan 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
    Beckman Research Institute of City of Hope)

  • Huilin Huang

    (Sun Yat-sen University Cancer Center)

  • Hengyou Weng

    (Guangzhou Medical University
    Guangzhou National Laboratory
    Bioland Laboratory)

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.

Suggested Citation

  • 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 & Chen, 2025. "m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58966-1
    DOI: 10.1038/s41467-025-58966-1
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    References listed on IDEAS

    as
    1. Liran I. Shlush & Amanda Mitchell & Lawrence Heisler & Sagi Abelson & Stanley W. K. Ng & Aaron Trotman-Grant & Jessie J. F. Medeiros & Abilasha Rao-Bhatia & Ivana Jaciw-Zurakowsky & Rene Marke & Jessi, 2017. "Tracing the origins of relapse in acute myeloid leukaemia to stem cells," Nature, Nature, vol. 547(7661), pages 104-108, July.
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