Physical Sciences Division
Published August 15, 2025 | Version v1
Journal article Metadata-only

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

Creators

  • 1. University of Chicago
  • 2. City of Hope

Description

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.

Data availability

RNA-seq data are accessible at the GEO repository, under accession number GSE282823 (https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE282823). All the software and packages used in this article are publicly available. The codes for sequencing data analysis have been publicly available on Zenodo (DOI: 10.5281/zenodo.15548979). All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

Additional details

Identifiers

DOI
10.1126/sciadv.adv7648
Other
oai:uchicago.tind.io:16168

Funding

National Institutes of Health
R01 HL155909
National Institutes of Health
RM1 HG008935
National Institutes of Health
R01 CA243386
National Institutes of Health
R01 CA271497

UChicago Information

Division(s)
Biological Sciences Division, Physical Sciences Division
Department(s)
Biochemistry and Molecular Biology, Biophysical Sciences, Chemistry, Radiation and Cellular Oncology
Center(s) or Institute(s)
Institute for Biophysical Dynamics, Ludwig Center for Metastasis Research