Breakthrough in acute myeloid leukemia treatment targets stem cells

Acute myeloid leukemia is one of the most deadly cancers. The leukemic stem cells that cause the disease are highly resistant to treatment. A team from the University of Geneva (UNIGE), Geneva University Hospitals (HUG) and INSERM has made a breakthrough by identifying the genetic and energetic properties of these stem cells, in particular a specific iron-utilization process. Blocking this process can kill or weaken these stem cells without affecting healthy cells. Science Translational Medicinepaving the way for new therapeutic strategies.

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 cases under 60 years of age and 85% of cases over 60 years of age.

This poor prognosis is thought to be due to the presence of so-called “dormant” or “quiescent” leukemia stem cells (LSCs) that escape chemotherapy. These cells are often invisible, but can “wake up” and reactivate the disease after seemingly successful treatment. Therefore, developing therapies targeting these cells is a major research challenge. However, the mechanisms that control them are poorly understood.

By identifying the specific genetic and metabolic signatures of LSCs, the UNIGE, HUG and Inserm teams are providing new insights and ways to combat the disease. Science Translational MedicinePaving the way for new therapeutic targets and their clinical applications.

Distinctive genetic signatures

''Using advanced bioinformatics techniques and in collaboration with Dr. Petros Tsantouris' team at the HUG Department of Oncology and Precision Oncology, we first determined that these quiescent cells contain a unique genetic signature of 35 genes. Using this signature in a large clinical database of AML patients, we were able to show that this signature is strongly associated with disease prognosis.“This is a promising new approach to cancer treatment,” explains study leader Jérôme Tamburini, Associate Professor at the Faculty of Medicine of the Swiss National Cancer Center (SCCL) Leman and the Centre for Translational Research in Oncology and Hematology (CRTOH), and physician in the Oncology Department at HUG.

Blocking certain nutrients

The study also uncovered metabolic differences between dormant and active leukemia stem cells. Typically, cells undergo chemical reactions to survive and break down nutrients to generate energy. This involves “autophagy,” a process in which cells recycle cellular components to generate new ones and provide energy when external nutrients are scarce. The scientists found that dormant leukemia stem cells rely on “ferritinophagy,” a specific form of autophagy that targets ferritin, the main iron storage molecule.

''This process is mediated by a protein called NCOA4, which controls the availability of iron in cells. Inhibiting it genetically or chemically makes leukemia cells more likely to die, especially dormant stem cells, while leaving healthy blood stem cells intact.” clarified INSERM researcher Clément Laroux, former postdoctoral researcher in Jérôme Tamburini's group, now a postdoctoral researcher at the Toulouse Cancer Research Center and first author of the study.

Towards clinical trials

Experiments conducted in mouse models confirmed that inhibiting the NCOA4 protein reduced tumor growth, survival, and self-renewal of leukemic stem cells. Therefore, targeting ferritinophagy via this inhibitory pathway may be a promising therapeutic strategy. The compound used to inhibit NCOA4 is in early stages of development for future clinical trials under the guidance of Jun Xu, a professor at Sun Yat-sen University in China, one of the study's co-authors.

The next step for the UNIGE team is to further investigate the mechanisms of ferritinophagy and its connection to mitophagy, another important mechanism in the control of LSCs. This new phase of research is supported by the Swiss Cancer League.