m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability
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 6-methyladenosine (m6A) modification as a...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58966-1 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Feng Huang |
| collection | DOAJ |
| description | 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 6-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. |
| format | Article |
| id | doaj-art-b51ba57573974f3ca95ccd6dab7f89e0 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b51ba57573974f3ca95ccd6dab7f89e02025-08-20T01:49:39ZengNature PortfolioNature Communications2041-17232025-05-0116111810.1038/s41467-025-58966-1m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerabilityFeng Huang0Yushuai Wang1Xiuxin Zhang2Weiwei Gao3Jingwen Li4Ying Yang5Hongjie Mo6Emily Prince7Yifei Long8Jiacheng Hu9Chuang Jiang10Yalin Kang11Zhenhua Chen12Yueh-Chiang Hu13Chengwu Zeng14Lu Yang15Chun-Wei Chen16Jianjun Chen17Huilin Huang18Hengyou Weng19The First Affiliated Hospital, The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Medical UniversityGuangzhou National LaboratoryBioland LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryGuangzhou National LaboratoryDepartment of Systems Biology and Center for RNA Biology and Therapeutics, Beckman Research Institute of City of HopeState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterBioland LaboratoryGuangzhou National LaboratoryState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Systems Biology and Center for RNA Biology and Therapeutics, Beckman Research Institute of City of HopeDivision of Developmental Biology, Cincinnati Children’s Hospital Medical CenterDepartment of Hematology, The Fifth Affiliated Hospital of Guangzhou Medical UniversityDepartment of Systems Biology and Center for RNA Biology and Therapeutics, Beckman Research Institute of City of HopeDepartment of Systems Biology and Center for RNA Biology and Therapeutics, Beckman Research Institute of City of HopeDepartment of Systems Biology and Center for RNA Biology and Therapeutics, Beckman Research Institute of City of HopeState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterThe First Affiliated Hospital, The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Medical UniversityAbstract 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 6-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.https://doi.org/10.1038/s41467-025-58966-1 |
| spellingShingle | 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 m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability Nature Communications |
| title | m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability |
| title_full | m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability |
| title_fullStr | m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability |
| title_full_unstemmed | m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability |
| title_short | m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability |
| title_sort | m6a igf2bp3 driven serine biosynthesis fuels aml stemness and metabolic vulnerability |
| url | https://doi.org/10.1038/s41467-025-58966-1 |
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