Acute myeloid leukemia (AML) is the most common cancer of the blood and bone marrow in adults. Caused by an increase in immature cells that rapidly destroy and replace healthy blood cells (red blood cells, white blood cells and platelets), AML is fatal in half of those affected under the age of 60 and in 85% of those over the age of 60. The leukemic stem cells responsible for the disease are highly resistant to treatment. This poor prognosis may be due to the presence of so-called “dormant” or “quiescent” leukemic stem cells (LESCs), which evade chemotherapy. Often invisible, these cells can “wake up” and reactivate the disease after a seemingly successful treatment cycle. Developing therapies that target these cells is therefore a major research challenge. However, the mechanisms that control them are poorly understood.
A team from the University of Geneva, Geneva University Hospital, and INSERM has made a breakthrough by identifying some of the genetic and energetic characteristics of these stem cells, in particular a specific process of iron utilization. This process could be blocked, leading to the death or weakening of these stem cells without affecting healthy cells. These findings, published in Science Translational Medicine, pave the way for new therapeutic strategies. Using advanced bioinformatics, the scientists were the first to establish that these quiescent cells contain a unique genetic signature composed of 35 genes. When they ran this signature in large clinical databases of AML patients, they were able to show that this signature was strongly linked to the prognosis of the disease.
The study also highlights a metabolic difference between dormant and active leukemic stem cells. In general, to survive, cells trigger chemical reactions that allow them to break down nutrients and then produce energy. This also involves “autophagy”, a process that allows cells to recycle cellular components to generate new ones and provide energy when external nutrients are lacking. Scientists have found that dormant leukemic stem cells depend on “ferritinophagy”, a specific form of autophagy that targets ferritin, the main iron storage molecule. This process is mediated by a protein called NCoA4/ARA70. This protein was originally identified as a co-activator for the androgen receptor (AR-alpha) and the peroxisome receptor PPAR-gamma.
It has since been shown to bind directly to intracellular ferritin and the autophagy complex component ATG8. By inhibiting it, either genetically or chemically, researchers have observed that leukemic cells, especially dormant stem cells, are more likely to die, while healthy blood stem cells remain intact. Experiments in mouse models have confirmed that blocking NCoA4 reduces tumor growth, viability, and self-renewal of leukemic stem cells. Targeting ferritinophagy through this inhibition pathway could therefore be a promising therapeutic strategy. The compound used to block NCoA4, a chimera derivative of an isoquinoline and a phenyl-benzimidazole moieties and temporarily labeled 9a, is in early development for future clinical trials.
Another compound that appears to interact with NCoA4 is ganoderic acid, a steroid substance isolated from the mushroom Ganoderma lucidum that has antitumor and anti-inflammatory properties. Very recently, another natural substance, the alkaloid nuciferine from the lotus (Nymphaea cerulea), was found to be able to inhibit NCoA4-mediated ferritinophagy. So, in addition to the possibility of engineering synthetic compounds directed against NCoA4, there is also the possibility of exploring the “exterminated mine” of natural plant compounds. The next step for scientists will be to further explore the mechanisms of ferritinophagy and its association with mitophagy (autophagy related to mitochondria), another key mechanism in the regulation of self-renewal of leukemic stem cells.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica.
Scientific references
Larrue C et al. Sci Translat Med, 2024; 16(757):eadk1731.
Le Y, Liu Q et al. Cell Death Discov. 2024 Jul 3; 10(1):312.
Gao X et al. Antioxidants (Basel) 2024 Jun 12; 13(6):714.
Lee A, Davis H. bioRxiv 2024 Jun 9:2024.06.09.597909.