FTO degrader inhibits acute myeloid leukemia by impairing ribosome biogenesis and translation

The fat mass and obesity-associated protein (FTO), an RNA m6A eraser, has been identified as a critical oncogenic factor in acute myeloid leukemia (AML). We presented the development of an FTO degrader(FP54) that selectively degrades FTO in AML cells, demonstrating superior efficacy both in vitro and in vivo. Mechanistically, FTO degradation increases m6A modifications on ribosome biogenesis related mRNAs and thus promotes YTHDF2-mediated degradation. This process impairs ribosome biogenesis and translation process, ultimately inhibiting AML progression. Overall design: We developed an FTO degrader FP54. We performed m6A-seq to identify m6A-hyper genes and found those genes were mostly enriched in ribosome biogenesis. Then we performed polysome-seq to identify which transcripted was influenced during translation process