Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by the uncontrolled proliferation of malignant hematopoietic stem and progenitor cells. METTL3, a key catalytic component within the m 6 A methyltransferase complex (alongside METTL14), is overexpressed in AML cells and plays a crucial role in promoting cancer. However, effective pharmacological targeting of the RNA m 6 A transferase core complex remains a challenge.
This new research published in the Genes & Diseases journal by a team from the University of Florida evaluates the anti-leukemic activity of a Von Hippel-Lindau (VHL)-recruiting METTL3 PROteolysis TArgeting Chimera (PROTAC), ZW27941.
The research team initially screened a library of VHL-directed METTL3 degraders against a panel of AML cell lines and identified ZW27941. ZW27941 was shown to degrade METTL3/METTL14 in a concentration- and time-dependent manner, requiring proteasomal and ubiquitin ligase activities and VHL binding. In vitro studies demonstrated that ZW27941 not only exhibited anti-tumor effects on AML cell lines but also inhibited cancer cell proliferation, promoted cell apoptosis, and triggered G0/G1 cell cycle arrest.
Further analysis demonstrated a dose-dependent reduction in c-Myc expression following ZW27941 treatment, which implicates the likely involvement of METTL3 in c-Myc regulation. Differential expression of 1911 genes was noted in AML cells following ZW27941 treatment, with a notable proportion being down-regulated. Additionally, this study also suggests that METTL3 plays a role in regulating translation through an m 6 A-independent mechanism. Furthermore, GO and KEGG analyses indicated that the down-regulated genes following ZW27941 treatment were enriched in metabolic processes, cell cycle regulation, and RNA processing pathways.
Importantly, ZW27941 demonstrated synergistic or additive effects when combined with standard AML therapeutics, such as cytarabine and venetoclax.
Although this study warrants further optimization and validation in animal models to fully establish the therapeutic potential and safety of these degraders in vivo , it also presents an exciting case for the use of selective METTL3 degraders in the context of leukemia. In conclusion, this research holds promise as a novel therapeutic approach for AML, particularly when used in combination with existing treatments to enhance efficacy and overcome resistance mechanisms.
Reference
Title of Original Paper: Targeting METTL3 protein by proteolysis-targeting chimeras: A novel therapeutic approach for acute myeloid leukemia
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2024.101452
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