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New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.
Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.
The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.
The researchers described this work in Nature.
“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.
“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”
In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.
The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.
The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.
Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.
Having found a potential target in METTL3, the researchers investigated how it worked.
They 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 which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.
The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.
“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.
“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.” 
New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.
Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.
The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.
The researchers described this work in Nature.
“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.
“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”
In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.
The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.
The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.
Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.
Having found a potential target in METTL3, the researchers investigated how it worked.
They 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 which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.
The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.
“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.
“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”
New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.
Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.
The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.
The researchers described this work in Nature.
“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.
“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”
In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.
The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.
The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.
Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.
Having found a potential target in METTL3, the researchers investigated how it worked.
They 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 which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.
The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.
“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.
“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”