Researchers have revealed new ideas about how acute myeloid leukemia (AML) develops and progresses, according to a study published in Molecular cell on July 20, 2021. They describe a mechanism by which AML cells regulate a cancer-related protein, mutant IDH2, to increase the accumulation of cancer cells in the blood, a hallmark of the disease. This improved understanding of the mechanism related to HDI2 in AML will allow physicians to better understand how current IDH2-targeted drugs work to ultimately improve treatments for patients with AML.
AML is a cancer of blood cells which can occur when immature white blood cells, cells that normally fight infections, acquire certain genetic mutations that cause them to multiply rapidly and accumulate in the bone marrow and blood. It is the most common acute leukemia in adults and usually gets worse quickly if left untreated.
This cancer can be driven by genetic mutations leading to the production of cancer-related mutant proteins, such as mutant IDH2 and IDH1. Normal HDI proteins are important in cellular metabolism and play a role in energy production from the breakdown of food molecules. The mutant forms of IDH proteins, which are found in AML cells, take on an additional role in making a cancer-causing molecule called 2-HG. 2-HG blocks the maturation of white blood cells, driving the development of leukemia.
Although 2-HG can drive the development of cancer, at high concentrations it becomes toxic and kills cancer cells. Researchers at the Comprehensive Center for Cancer Medicine at the University of Chicago, with collaborators, were interested in learning how mutant HDI2 drives the development of AML and how leukemia cells are able to regulate production. of 2-HG to promote spread and prevent cell death.
The research team, led by Jing Chen, a doctor of medicine, professor of medicine, discovered that AML cells are able to modify the mutant IDH2 and regulate its activity, thus controlling the amount of 2-HG. which can produce. They determined the 2-HG concentration threshold that allows it to move from a cancer-causing agent to a cancer-killing agent.
Using human AML cells, they found that the mutant IDH2 was controlled by a major regulator, called FLT3, which can activate and deactivate proteins through a modification process. The team defined the series of events initiated by FLT3 that led to a chemical modification, called acetylation, of the mutant IDH2, and found that this type of modification blocks its activity and decreases the amount of 2-HG. in the cell, which allows the AML to bypass the cell. death.
“Our studies show that different intracellular concentrations of 2-HG correlate with critical cellular functions that can mean the life or death of cancer cells,” Chen said. “We also elucidated the different regulatory mechanisms of protein variants, mutant IDH1 and mutant IDH2, in AML. This complete understanding of AML driven by IDH mutant proteins allows us to better understand the mechanisms of action of therapies targeted at the ‘AML’.
Treatments for AML include chemotherapy, radiation, and disease-specific medications. protein AML drivers. In fact, mutants targeting IDH2 and IDH1 mutants have been approved by the FDA to treat AML that has relapsed or been resistant to other drugs. For example, enasidenib is a small molecule that binds to and inhibits the IDH2 inhibitor. It has been shown to increase the maturation of leukemic cells and reduce the number of leukemic cells in animal models. This latest discovery describing how AML cells regulate mutant HDI proteins and the production of 2-HG provides new insights into how mutant HDI-targeted drugs work against AML. Studies like these may allow the development of better treatment options for patients with AML.
Dong Chen et al, lysine acetylation restricts IDH2 mutant activity to optimize transformation into AML cells, Molecular cell (2021). DOI: 10.1016 / j.molcel.2021.06.027
University of Chicago
Citation: New findings reveal how acute myeloid leukemia walks between growth and cell death (2021, July 20) recovered on July 20, 2021 at https://medicalxpress.com/news/2021-07-discoveries -reveal-acute-myeloid-leukemia. html
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