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

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-05-06 DOI:10.1038/s41467-025-58966-1

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

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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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m6A/ igf2bp3驱动的丝氨酸生物合成促进AML干细胞和代谢易损性

氨基酸的代谢重编程代表了癌细胞的脆弱性，但急性髓性白血病（AML）和白血病干细胞/起始细胞（LSCs/LICs）中丝氨酸代谢的机制尚不清楚。在这里，我们发现RNA n6 -甲基腺苷（m6A）修饰是AML中丝氨酸生物合成的关键调节因子。通过CRISPR/Cas9筛选，我们发现m6A调节因子IGF2BP3或METTL14的缺失使AML细胞对丝氨酸和甘氨酸（SG）的剥夺敏感。IGF2BP3识别关键丝氨酸合成途径（SSP）基因（如ATF4、PHGDH、PSAT1） mrna上的m6A，稳定这些转录本，维持丝氨酸的产生，以满足AML细胞和LSCs/ lic的高代谢需求。IGF2BP3沉默联合饮食SG限制在体外和体内有效抑制AML，而其缺失则保留正常的造血功能。我们的研究结果揭示了m6A修饰在AML丝氨酸代谢易损性中的关键作用，并强调了IGF2BP3/m6A/SSP轴是一个有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.