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

Area of Science:

• Molecular Oncology
• Epigenetics
• Cancer Therapeutics

Background:

• Targeting ribosome biogenesis and protein translation is a key strategy in cancer therapy.
• The fat mass and obesity-associated protein (FTO), an RNA N⁶-methyladenosine (m⁶A) demethylase, is implicated as an oncogenic factor in acute myeloid leukemia (AML).

Purpose of the Study:

• To develop and evaluate a novel FTO degrader for selective targeting of AML cells.
• To investigate the mechanism by which FTO degradation impacts ribosome biogenesis and AML progression.

Main Methods:

• Development of a selective FTO degrader compound.
• In vitro and in vivo efficacy studies in AML models.
• Analysis of m⁶A modifications, mRNA decay, and ribosome biogenesis pathways.

Main Results:

• The developed FTO degrader demonstrated superior efficacy in selectively degrading FTO in AML cells, both in vitro and in vivo.
• FTO degradation led to increased m⁶A modifications on mRNAs involved in ribosome biogenesis.
• This resulted in YTHDF2-mediated mRNA decay, disrupting ribosome biogenesis and protein translation, thereby inhibiting AML progression.

Conclusions:

• The FTO degrader is a potent tool for studying FTO's role in cancer.
• This FTO degrader represents a potential therapeutic strategy for developing selective anticancer treatments for AML.