Year: 2025
Type: article
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. Serine metabolism is essential for leukemogenesis and stemness in acute myeloid leukemia (AML). Here the authors show that targeting IGF2BP3 disrupts the serine synthesis pathway in AML cells in an RNA N6-Methyladenosine modification dependent manner, sensitizing AML cells to serine and glycine deprivation.
Source: Nature Communications
Authors: 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, Hengyou Weng
Institutions: First Affiliated Hospital of Guangzhou Medical University, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, State Key Laboratory of Respiratory Disease, Guangzhou Laboratory, Guangzhou Medical University, Shantou University Medical College, University of Science and Technology of China, City of Hope, Beckman Research Institute, Sun Yat-sen University, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Cincinnati Children's Hospital Medical Center, Jinan University, City Of Hope National Medical Center
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
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, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W4410118602