2. Academic Validation
  3. FTO degrader impairs ribosome biogenesis and protein translation in acute myeloid leukemia

FTO degrader impairs ribosome biogenesis and protein translation in acute myeloid leukemia

  • Sci Adv. 2025 Aug 15;11(33):eadv7648. doi: 10.1126/sciadv.adv7648.
Wenlong Li 1 2,  Yutao Zhao 1 2,  Dong Wu 3 4,  Zhenhua Chen 3 4 5,  Ying Qing 3 4,  Fan Yang 1 2,  Fei Ji 6 7,  Linda Zhang 1 2,  Lillian Sau 3 4,  Jianjun Chen 3 4,  Chuan He 1 2
Affiliations

Affiliations

  • 1 Departments of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
  • 2 Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
  • 3 Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
  • 4 Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
  • 5 Department of Hematology, The First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
  • 6 Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637, USA.
  • 7 Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
PMID: 40815637 DOI: 10.1126/sciadv.adv7648
Abstract

Targeting ribosome biogenesis and protein translation has emerged as a promising avenue for Cancer therapy. The fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) eraser, has been identified as an oncogenic factor in acute myeloid leukemia (AML). Here, we present the development of an FTO degrader that selectively degrades FTO in AML cells, demonstrating superior efficacy both in vitro and in vivo. We confirmed that FTO degradation increases m6A modifications on mRNAs associated with ribosome biogenesis, promoting their YTHDF2-mediated decay. This disruption of ribosome biogenesis and protein translation contributes to the inhibition of AML progression. Our findings highlight this FTO degrader as a valuable tool compound for elucidating the functional roles of FTO in Cancer and as a potential foundation for the development of selective Anticancer therapies.

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