Surprising new drug target discovered for acute myeloid leukemia
AML is the most common acute leukemia affecting adults, and its incidence increases with age.fitness Updated: Nov 28, 2017 13:02 IST
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterised by the rapid growth of abnormal white blood cells that build up in the bone marrow and interfere with the production of normal blood cells.
AML is the most common acute leukemia affecting adults, and its incidence increases with age. Mainstream AML treatments have remained unchanged for decades and fewer than one in three people survive the cancer.
But, now a study has found an unexpected new drug target for acute myeloid leukemia (AML) that could open new avenues to develop effective treatments against this potentially lethal disease. The scientists 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, finding which were essential for AML survival. The researchers ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA.
Amongst these, METTL3 was one of the genes with the strongest effect. They found that while it was essential for the survival of AML cells, it was not required for healthy blood cells, making it a good potential drug target.
Talking about the research, Professor Tony Kouzarides, joint project leader from the Gurdon Institute, University of Cambridge, said, “New treatments for AML are desperately needed and we have been looking for genes that would be good drug targets. 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.”
For proteins to be produced in a cell, the DNA is transcribed into messenger RNA, which is then translated into the proteins that the cell needs. However, modifications to the RNA can control if a protein is produced. This is a recently-discovered type of gene regulation called RNA editing.
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. Then, as RNAs were produced, the METTL3 protein added methyl groups to their middle section, something which had not been previously observed.
The scientists found that these middle methyl groups increased the ability of the RNAs to be translated into proteins. They then showed 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.
One of the first authors on the study from the Wellcome Trust Sanger Institute, Dr Konstantinos Tzelepis, noted, “This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA. 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.” The study was published in the journal, Nature.
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First Published: Nov 28, 2017 13:02 IST