Achilles heel found that could break new ground in the fight against leukemia

In a paper published in the journal Redox Biology, researchers demonstrated that leukemia cells lack certain mechanisms that prevent iron-triggered programmed cell death, which could be exploited for treatment of the disease with experimental drugs.

As a result of collaborative work between the Institute of Biomedicine of Buenos Aires (CONICET – Max Planck Partner) and the Josep Carreras Leukemia Research Institute in Barcelona, a team of researchers discovered that they could trigger the death of acute lymphoblastic leukemia cancer cells using experimental drugs. The work was recently published in Redox Biology, the leading journal in the field of oxidative stress and cancer.  

Human tumors are characterized, among other things, by their ability to avoid cell death. This, in contrast, is common in healthy organs, where damaged or aged cells are eliminated by programmed cell death processes.

Ferroptosis is a form of cell death generated by iron-mediated fat oxidation, which triggers lethal damage to cell membranes. To avoid ferroptosis, cells resort to two mechanisms: one that requires glutathione (the main cellular antioxidant), and one that does not. 

“One of the functions of glutathione is to participate in the detoxification of harmful compounds generated from lipids (fats). The formation of these toxic compounds is mediated by iron, and their accumulation ends up damaging cell membranes. This damage triggers a type of cell death that is called ferroptosis due to iron dependence”, explains Dr. Lucas Pontel, head of the “Cancer Metabolism” group.

These compounds are very dangerous, and most cells – normal and cancerous – have a second protection system that can replace glutathione if necessary, and which depends mainly on the FSP1 protein. “We were surprised to see that acute lymphoblastic leukemia cells were very sensitive to drugs that block glutathione generation, much more so than cancer cells from other tissues and even normal cells”, adds Pontel, leader of the research.

The researchers detected that both in acute lymphoblastic leukemia cells and in patient samples, the gene coding for FSP1 was methylated. This epigenetic modification prevents expression of the gene, and by silencing it leaves the leukemia cells with only one shield to avoid ferroptosis: the glutathione-dependent one. This explains their exquisite sensitivity to drugs that block glutathione synthesis.

This work originated from a bioinformatics exploration carried out by Agustín Morellato, a CONICET doctoral fellow in Pontel’s group. Agustín observed that cell lines derived from hematopoietic tumors showed lower tolerance to inactivate glutathione synthesis. With this information, Pontel headed the project in Dr. Manel Esteller’s Cancer Epigenetics group (at the Josep Carreras Leukemia Research Institute, Barcelona), using the tools available there to study this type of tumors. In collaboration with the group of Dr. Gaël Roué (from the same Catalan institute), the scientists tested the hypothesis in a model of tumorigenesis in fertilized chicken eggs. This research model is an alternative to the use of animals and makes it possible to evaluate in vivo tumor growth and response to drugs in early stages of biomedical research.  

Acute lymphoblastic leukemia in Argentina represents 37% of all pediatric cancers, including young adults. While overall survival in the pediatric population is almost 90%, in the case of adults it drops to half. Currently, conventional chemotherapy is still widely used but often produces long-term side effects. This highlights the need to find more selective targets to treat this type of disease. In this sense, identifying the specific characteristics of leukemic cells becomes crucial because it can guide personalized treatments giving very good results.