FTO regulates ELK3-mediated metabolic rewiring and represents a unique therapeutic target in T cell leukemia
Understanding the regulation of N6-methyladenosine (m<sup>6</sup>A), the prominent internal modification in mRNA, fosters the development of potential therapeutic strategies for human cancers. While the m<sup>6</sup>A 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 <i>FTO</i>, but not <i>ALKBH5</i>, significantly suppresses leukemia initiation and progression. Mechanistic analysis reveals that FTO heightens <i>ELK3</i> mRNA stability in an m<sup>6</sup>A-dependent manner. Elevated ELK3 in turn transcriptionally activates the expression of glycolytic genes. Pharmacological inhibition of FTO suppresses <i>ELK3</i> 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.
Authors
- Panagiotis Ntziachristos (ORCID: https://orcid.org/0000-0001-6374-8954)
- Ting Xie (ORCID: https://orcid.org/0000-0003-4769-986X)
- Hudan Liu (ORCID: https://orcid.org/0000-0003-1362-6048)
- Donghai Wang (ORCID: https://orcid.org/0000-0001-6119-8557)
- Haojian Zhang (ORCID: https://orcid.org/0000-0002-9394-9383)
- Guoliang Qing (ORCID: https://orcid.org/0000-0002-7892-2860)
- Yuan Wang (ORCID: https://orcid.org/0000-0001-8385-0745)
- Yu Liu (ORCID: https://orcid.org/0000-0001-8928-2558)
- Hao Huang (ORCID: https://orcid.org/0000-0002-3144-809X)
- Jin Xu
- Huabing Li (ORCID: https://orcid.org/0000-0003-3573-6803)
- Chuan Gao (ORCID: https://orcid.org/0000-0002-1399-8450)
- Xinlu Li (ORCID: https://orcid.org/0000-0002-0766-4788)
- Jin-lian Luo
- Mengjie Yang (ORCID: https://orcid.org/0009-0000-7836-3678)
- Z. Chen (ORCID: https://orcid.org/0009-0003-4801-1331)
- Jinyan Huang (ORCID: https://orcid.org/0000-0002-8053-0209)
- Yun Zhao
Institutions
- Shanghai Jiao Tong University (CN)
- Ghent University Hospital (BE)
- Ghent University (BE)
- Wuhan University (CN)
- Soochow University (CN)
- Shanghai Children's Medical Center (CN)
- Zhongnan Hospital of Wuhan University (CN)
- State Key Laboratory of Oncogene and Related Genes (CN)
- First Affiliated Hospital Zhejiang University (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-05-28
- DOI
- https://doi.org/10.1126/sciadv.adq3052
- Citations
- 3
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- National Natural Science Foundation of China
- Wuhan University
- Fundamental Research Funds for the Central Universities