A new study has found that inhibiting the METTL3 gene destroys human and mouse acute myeloid leukemia (AML) cells without harming non-leukemic blood cells. The findings suggest an unexpected new drug target for AML and may open new avenues to develop effective treatments for the disease. Researchers report in the journal Nature the methyltransferase enzyme METTL3 may be targetable.
The researchers used CRISPR-Cas9 gene editing technology to screen cancer cells for vulnerable points. They created mouse leukemia cells with mutations in the genes that may be targeted in human AML cells and systematically tested each gene. The researchers ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. However, METTL3 was one of the genes with the strongest effect.
“We found a new mechanism by which RNA modifying enzymes (specifically METTL3, which methylates m6A) function, which involves their recruitment to chromatin and specifically gene promoters. The second surprise was that this new pathway is important for the maintenance of AML. This is very good news for targeting this pathway in the treatment of this disease,” said study investigator Tony Kouzarides, PhD, a professor of cancer biology and a member of the Department of Pathology at University of Cambridge in the United Kingdom.
This current study demonstrated that downregulation of METTL3 resulted in cell cycle arrest. It also resulted in differentiation of leukemic cells and failure to establish leukemia in immunodeficient mice. Kouzarides said he hopes these new findings will inspire pharmaceutical entities to find drugs that specifically inhibit METTL3 to treat AML.
“Characterization of RNA modifications is a very exciting new area of biology, so finding that it represents a target for cancer is very encouraging and exciting. All the information is now in place to start drug discovery, which could take only several years to reach phase one if all goes well,” Kouzarides told OncoTherapy Network.
The researchers discovered that the protein produced by METTL3 bound to the beginning of 126 different genes, including several required for AML cell survival. As RNAs were produced, the METTL3 protein added methyl groups to their middle section, something that had not been previously observed. The researchers found that these middle methyl groups increased the ability of the RNAs to be translated into proteins. They also discovered that when METTL3 was inhibited, no methyl groups were added to the RNA.