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

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 <i>N</i>⁶-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.