According to a recent article in MedicalXpress, researchers led by professor of medicine Dr. Jing Chen uncovered new data showing how acute myeloid leukemia (AML) becomes active and progresses. The study was published by Molecular Cell on July 20, 2021.
AML can be described as a cancer of the blood and bone marrow in which the bone marrow produces infection-fighting white blood cells (WBC).
However, AML occurs when myeloblasts, which are WBC that have not fully developed, acquire mutations and multiply rapidly. In addition, platelets and red blood cells are affected as they are also produced by the bone marrow.
About IDH2 Mutations
AML can be caused by IDH1 and IDH2 genetic mutations. The researchers identified the mechanism used by AML cells to regulate the mutant IDH2, a cancer-related protein that increases blood cancer cells. IDH mutations can be found in twenty-five percent of AML patients.
These gene variants represent a permanent change in the DNA sequence that produces a gene. The normal IDH proteins are critical to cell metabolism due to their involvement in producing energy. Energy is produced when molecules from our food are broken down. Proteins are one of four categories of molecules that make up the food we consume. The other categories are carbohydrates, lipid, and nucleic acid.
Researchers identified the mutant IDH proteins they discovered in the AML cells as having an additional function. The function produces a molecule called 2-HG which prevents WBC from maturing and drives leukemia.
Taking it a step further, 2-HG becomes toxic when highly concentrated, causing it to kill cancer cells.
This was of interest to the Chicago University Cancer Center researchers. The team and their collaborators studied:
- The mutant IDH2 and how it drives AML development, and
- How leukemia cells regulate 2-HG to promote the spread of cancer yet avoids cell death.
Dr. Chen and his team found that the AML cells can modify the IDH2 mutant as well as regulate activity. In this way, AML cells are able to control the 2-HG that is produced. More importantly, the researchers were able to determine the appropriate concentration of 2-HG that enables switching from an agent that causes cancer to an agent that kills cancer.
The Master Regulator
Using AML cells the research team discovered that mutant IDH2 was actually controlled by FLT3 which is a master regulator. It can activate or deactivate proteins by way of a modification process.
The team studied the events surrounding FLT3 that led to acetylation, a chemical modification of mutant IDH2. They discovered that this modification blocks the activity of IDH2, decreasing the amount of 2-HG in a cell.
Dr. Chen stated that their studies proved that concentrations of 2-HG correspond to certain cellular functions affecting the life or death of cancer cells. The team also elucidated IDH1 and IDH2 balancing mechanisms.
Currently, the FDA has approved inhibitors targeting IDH1 and IDH2 to treat patients who have relapsed or who exhibited a resistance to other lines of AML medication. Enasidenib is one of the newer medications approved as an inhibitor of IDH2. The drug was investigated in studies using animal models. By binding and inhibiting the IDH2 mutant it reduced leukemic cells.
Dr. Chen said that their improved comprehension of the IDH2 mechanism in AML allows doctors to have a better understanding of how IDH2 targeting therapies act against AML.
