FTO regulates ELK3-mediated metabolic rewiring and represents a unique therapeutic target in T cell leukemia

被引：0

作者：

Huang, Hao ^{[1
,2
,3
]}

Li, Xinlu ^{[2
]}

Luo, Jinlian ^{[2
]}

Gao, Chuan ^{[2
]}

Yang, Mengjie ^{[2
]}

Xu, Jin ^{[2
]}

Xie, Ting ^{[2
]}

Chen, Zhi ^{[2
]}

Wang, Donghai ^{[2
]}

Wang, Yuan ^{[4
]}

Li, Hua-Bing ^{[5
]}

Huang, Jinyan ^{[6
]}

Liu, Yu ^{[7
]}

Zhang, Haojian ^{[2
,3
]}

Ntziachristos, Panagiotis ^{[8
]}

Zhao, Yun ^{[9
]}

Qing, Guoliang ^{[2
,3
]}

Liu, Hudan ^{[1
,2
,3
]}

机构：

[1] Wuhan Univ, Zhongnan Hosp, Dept Hematol, State Key Lab Metab & Regulat Complex Organisms, Wuhan, Peoples R China

[2] Wuhan Univ, Med Res Inst, Frontier Sci Ctr Immunol & Metab, Wuhan, Peoples R China

[3] Wuhan Univ, Taikang Ctr Life & Med Sci, Wuhan, Peoples R China

[4] Wuhan Univ, Sch Basic Med Sci, Dept Physiol, Wuhan, Peoples R China

[5] Shanghai Jiao Tong Univ, Shanghai Inst Immunol, State Key Lab Oncogenes & Related Genes, Sch Med, Shanghai, Peoples R China

[6] Zhejiang Univ, Affiliated Hosp 1, Ctr Biomed Big Data, Sch Med, Hangzhou, Peoples R China

[7] Shanghai Jiao Tong Univ, Pediat Translat Med Inst, Shanghai Childrens Med Ctr, Sch Med, Shanghai, Peoples R China

[8] Univ Ghent, Fac Med & Hlth Sci, Dept Biomol Med, Leukemia Therapy Resistance Lab, Ghent, Belgium

[9] Soochow Univ, Cyrus Tang Med Inst, Natl Clin Res Ctr Hematol Dis, Suzhou, Peoples R China

来源：

SCIENCE ADVANCES | 2025年 / 11卷 / 22期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; MOLECULAR-MECHANISMS; DEMETHYLASE;

D O I：

10.1126/sciadv.adq3052

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Understanding the regulation of N6-methyladenosine (m6A), the prominent internal modification in mRNA, fosters the development of potential therapeutic strategies for human cancers. While the m6A demethylases FTO and ALKBH5 are recognized for their crucial roles in various cancers, their impact on lymphoid leukemia remains uncertain. Using T cell acute lymphoblastic leukemia (T-ALL) as a model system, we identify FTO as a unique vulnerability in T cell leukemia. Knockout of FTO, but not ALKBH5, significantly suppresses leukemia initiation and progression. Mechanistic analysis reveals that FTO heightens ELK3 mRNA stability in an m6A-dependent manner. Elevated ELK3 in turn transcriptionally activates the expression of glycolytic genes. Pharmacological inhibition of FTO suppresses ELK3 expression, hampers glycolysis and manifests remarkable antileukemia efficacy. Our findings unravel the crucial role of FTO in T-ALL and highlight the FTO-ELK3 axis as a key nodule during leukemogenesis, thereby providing a fundamental basis to harness selective FTO antagonist for T-ALL therapeutics.

引用

页数：16

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