Acute myeloid leukemia is one of the deadliest cancers. This is largely due to the high resistance of leukemic stem cells to treatments.
Cancer cell created in 3D.
© Fotalia
A team from the University of Geneva (UNIGE), the Geneva University Hospitals (HUG), and Inserm has made a major breakthrough by identifying certain genetic and energetic characteristics of these cells, specifically a unique process of iron utilization. The researchers also succeeded in blocking this process, leading to the death or weakening of the leukemic stem cells without affecting healthy cells.
These results, published in
Science Translational Medicine, pave the way for new therapeutic strategies.
Acute myeloid leukemia (AML) is the most common blood and bone marrow cancer in adults. Caused by the accumulation of immature cells that rapidly destroy and replace healthy blood cells (red blood cells, white blood cells, and platelets), it is fatal for half the affected individuals under 60, and for 85% of those over that age.
This grim prognosis is largely due to the presence of so-called "dormant" or "quiescent" leukemic stem cells (LSCs), which escape available chemotherapy treatments. Often invisible, they can "awaken" and reactivate the disease after a seemingly successful treatment. Developing therapies targeting them directly is thus a major research challenge. However, the mechanisms governing them remain poorly understood.
By identifying genetic and metabolic characteristics specific to LSCs, which can be targeted, a team from UNIGE, HUG, and Inserm provides new insights, as well as actionable avenues, for fighting the disease. These results, published in
Science Translational Medicine, open the way to a new therapeutic target and its clinical application.
A distinctive genetic signature
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Through advanced bioinformatics techniques and in collaboration with Dr. Petros Tsantoulis' team from the Oncology Department of the HUG Precision Oncology Services, we first established that these quiescent cells contain a unique genetic signature of 35 genes. Using this signature in large clinical databases of AML patients, we demonstrated that this signature was strongly linked to the prognosis of the disease," explains Jérôme Tamburini, Associate Professor in the Department of Medicine and the Translational Research Center in Onco-Hematology (CRTOH) of the Faculty of Medicine at UNIGE as well as the Swiss Cancer Center Léman (SCCL), and hospital-university deputy physician in the Oncology Service of HUG, who led this research.
Blocking a specific 'nutrient'
The study also highlights a metabolic difference between dormant and active leukemic stem cells. Generally, to survive, cells trigger chemical reactions to break down certain nutrients and produce energy. This also involves "autophagy," a self-digestion process allowing cells to continue feeding in the absence of external nutrients.
The scientists discovered that dormant leukemic stem cells depend on "ferritinophagy," a specific form of autophagy targeting ferritin, the main iron storage molecule.
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This process is mediated by a protein called NCOA4. It controls the availability of iron within cells. By inhibiting this protein, either genetically or chemically, we observed that leukemic cells, particularly the dormant stem cells, are more likely to die, while healthy blood stem cells remain intact," reveals Inserm researcher Clément Larrue, a former post-doctoral researcher in Jérôme Tamburini's group, currently a post-doctoral researcher at the Cancer Research Center of Toulouse and the study's first author.
Towards clinical trials
Experiments conducted with mouse models confirmed that blocking the NCOA4 protein reduces tumor growth, viability, and self-renewal of leukemic stem cells. Targeting ferritinophagy through this inhibition pathway could thus represent a promising therapeutic strategy. The compound used to block NCOA4 is in the early stages of development for upcoming clinical trials, led by one of the study's co-authors, Jun Xu, a professor at Sun Yat-Sen University in China.
For the UNIGE team, the next phase of research will involve further exploring the mechanisms of ferritinophagy and its relationship with mitophagy, another key regulatory mechanism of LSCs. This new research stage is supported by the Swiss Cancer League.