Acute myeloid leukemia (AML) is a severe cancer of the blood and bone marrow, often fatal. The disease is driven by leukemic stem cells that resist treatment and can become active again after therapy.
Researchers from the University of Geneva, University Hospital of Geneva, and Inserm have identified these stem cells’ critical genetic and metabolic traits, including a specific way they use iron. Targeting this process could weaken or kill these stem cells without harming healthy cells. This discovery, detailed in Science Translational Medicine, offers a new direction for developing treatments.
Researchers found that dormant leukemic stem cells have a unique set of 35 genes. This gene pattern is linked to how the disease progresses in AML patients, as shown in large clinical databases.
The study also discovered that dormant leukemic stem cells rely on a unique ” ferritinophagy ” process to get energy. This involves breaking down ferritin, an iron storage molecule, to help the cells survive.
Blocking a protein called NCOA4, which controls iron in cells, makes leukemic stem cells, especially dormant ones, more likely to die. In contrast, healthy blood stem cells stay safe.
Tests on mice show that blocking NCOA4 slows down tumor growth and affects leukemic stem cells. This approach could be a promising treatment. The compound to block NCOA4 is being developed for future clinical trials. Next, researchers at UNIGE will study how ferritinophagy and mitophagy affect these stem cells, with support from the Swiss Cancer League.
Targeting the unique traits of leukemic stem cells, such as their reliance on specific processes like ferritinophagy, offers a promising new approach to treating leukemia.
Inhibiting proteins like NCOA4 that help these stem cells survive can make them more likely to die while sparing healthy cells. This strategy could lead to more effective therapies and is moving toward clinical trials.
Journal reference:
- Jérôme Tamburini, Clément Larrue, et al., Targeting ferritinophagy impairs quiescent cancer stem cells in acute myeloid leukemia in vitro and in vivo models. Science Translational Medicine. DOI: 10.1126/scitranslmed.adk1731.