m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability
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 N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of m<sup>6</sup>A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies m<sup>6</sup>A 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 m<sup>6</sup>A modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/m<sup>6</sup>A/SSP axis as a promising therapeutic target.
Authors
- Lu Yang (ORCID: https://orcid.org/0000-0001-7952-0399)
- Yueh‐Chiang Hu (ORCID: https://orcid.org/0000-0002-7992-0525)
- Feng Huang (ORCID: https://orcid.org/0000-0002-8406-5068)
- Emily Prince (ORCID: https://orcid.org/0000-0002-8972-5248)
- 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)
- Chengwu Zeng (ORCID: https://orcid.org/0000-0002-1333-3918)
- Jiacheng Hu (ORCID: https://orcid.org/0000-0003-3630-5829)
- Chen Jiang (ORCID: https://orcid.org/0000-0003-4969-6128)
- Chun‐Wei Chen (ORCID: https://orcid.org/0000-0002-8737-6830)
- Hengyou Weng (ORCID: https://orcid.org/0000-0001-6474-2861)
- Jingwen Li (ORCID: https://orcid.org/0000-0003-1135-6611)
- Jianjun Chen (ORCID: https://orcid.org/0000-0003-3749-2902)
- Zhenhua Chen (ORCID: https://orcid.org/0000-0002-1381-0235)
- 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)
- Yalin Kang
Institutions
- University of Science and Technology of China (CN)
- Cincinnati Children's Hospital Medical Center (US)
- Sun Yat-sen University (CN)
- Jinan University (CN)
- Shantou University (CN)
- Guangzhou Experimental Station (CN)
- Second Affiliated Hospital of Guangzhou Medical 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)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-06
- DOI
- https://doi.org/10.1038/s41467-025-58966-1
- Citations
- 12
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 9.67
Funders
- National Natural Science Foundation of China
- National Institutes of Health
- Guangdong Provincial Pearl River Talents Program
- Sun Yat-sen University Cancer Center
- Basic and Applied Basic Research Foundation of Guangdong Province