mA/IGF2BP3驱动的丝氨酸生物合成助力急性髓系白血病的干性及代谢脆弱性。

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

作者信息

Huang Feng, Wang Yushuai, Zhang Xiuxin, Gao Weiwei, Li Jingwen, Yang Ying, Mo Hongjie, Prince Emily, Long Yifei, Hu Jiacheng, Jiang Chuang, Kang Yalin, Chen Zhenhua, Hu Yueh-Chiang, Zeng Chengwu, Yang Lu, Chen Chun-Wei, Chen Jianjun, Huang Huilin, Weng Hengyou

机构信息

The First Affiliated Hospital, The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China.

Guangzhou National Laboratory, Guangzhou, China.

出版信息

Nat Commun. 2025 May 6;16(1):4214. doi: 10.1038/s41467-025-58966-1.

DOI:10.1038/s41467-025-58966-1

PMID:40328743

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12056023/

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 N-methyladenosine (mA) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of mA regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies mA 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 mA modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/mA/SSP axis as a promising therapeutic target.

摘要

氨基酸的代谢重编程是癌细胞的一个弱点，然而急性髓系白血病（AML）以及白血病干细胞/起始细胞（LSCs/LICs）中丝氨酸代谢的潜在机制仍不清楚。在此，我们确定RNA N-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）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，稳定这些转录本并维持丝氨酸生成，以满足AML细胞和LSCs/LICs的高代谢需求。IGF2BP3沉默联合饮食SG限制在体外和体内均能有效抑制AML，而其缺失不影响正常造血。我们的研究结果揭示了m⁶A修饰在AML丝氨酸代谢弱点中的关键作用，并突出了IGF2BP3/m⁶A/SSP轴作为一个有前景的治疗靶点。