FTO regulates ELK3-mediated metabolic rewiring and represents a unique therapeutic target in T cell leukemia.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40435251.
- Also identified by DOI 10.1126/sciadv.adq3052 and PMC identifier 12118595.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Leukemia, T-Cell
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma