All human tumors originating from various tissues share a series of properties that define them, including the ability to prevent cell death.

Instead, healthy organs induce programmed cell death or apoptosis to balance their size and eliminate damaged cells. There is a specific and physiological cell death called ferroptosis that occurs induced by the oxidation of fat mediated by iron content.

Today, an article published in the journal Redox Biology, the journal of reference in the field of free radicals and cancer, by the group of Dr. Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute, ICREA Research Professor and Chairman of Genetics at the University of Barcelona, ​​and headed by Dr Lucas Pontel, shows that epigenetic changes prevent iron-associated programmed cell death in leukemia and show a new target for treatment with experimental drugs.

“Leukemia cells avoid dying because they have two floats, the metabolism of the biomolecule called glutathione and the FSP1 gene that acts as a shield against this death induced by iron and oxidation” – comments Dr. Esteller and adds – “Studying all these metabolic pathways we realized that in acute lymphoblastic leukemia (ALL) the activity of the FSP1 gene was epigenetically lost, so these cells were on the edge of the precipice of their programmed death. We only needed to give them a boost and that is what we did by administering them inhibitors of the glutathione pathway, such as L-BSO and RSL3, which rapidly induced the death of these malignant lymphocytes. In other words, this type of leukemia lives on the edge in terms of its tolerance towards ferroptosis and when you eliminate their last lifeline with a drug, these transformed cells die. This weak spot of acute lymphoblastic leukemia can therefore be explored in precision and personalized treatments for this disease, but it could also occur in other cancers. There are few clinical trials in oncology with glutathione inhibitors, but perhaps this type of work will arouse interest in the study and development of these promising experimental agents”, concludes the researcher.

In the same line, Dr. Pontel notes that “by exploring data from T-ALL and B-ALL patients, we detected that FSP1 is under epigenetic control. Thus, by determining the FSP1 epigenetic status in patients, we might be able to anticipate the success of a therapy based on drugs that induced ferroptosis”.

 

Article:

Pontel LB, Bueno-Costa A, Morellato AE, Carvalho-Santos J, Roué G, Esteller M. Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing. Redox Biology, DOI: 10.1016/j.redox.2022.102408, 2022.

Cancer is a disease characterized by the transformation of a healthy cell into a malignant one with very different characteristics, such as the ability to divide in an uncontrolled manner. In recent decades, much research has uncovered various molecular alterations responsible for this conversion from healthy to tumor tissue. However, we know little about the opposite process, that is being able to reverse a cancer cell turning it into a physiological, non-cancerous one, and what factors might mediate this process.

“We know that one strategy that human tumors have to dodge the effectiveness of drugs is to change their appearance, becoming another similar cancer but insensitive to the drug used. For example, leukemias of the lymphoid lineage are switched to the myeloid strain to escape treatment”, explains Dr. Esteller. With this idea in mind, they wanted to know more about the molecular pathways involved in these cellular metamorphoses and studied an in vitro model where leukemia cells can be forced to turn into a type of harmless immune cells called macrophages.

Experimental results showed that the reversal of the malignant cells into macrophages involved a profound change in the chemical changes occurring on their messenger RNAs, the carriers that help proteins formation. In particular, the changes affected the distribution of an epigenetic mark called methylated adenine. This change in the chemical accentuation of these molecules causes instability of the proteins that define the leukemia while favoring the appearance of differentiated proteins characteristic of the normal cell that is being born, the macrophage. This process appears to be controlled by the METTL3 gene, a manufacturer of chemical modifications targeting messenger RNA.

This line of research, though still in the preclinical stage, looks quite promising and is worth further exploring as a new approach in the fight against leukemia. In fact, as Dr. Esteller points out, “the first preclinical drugs against this target have already been developed in experimental models of malignant blood diseases, so we provide another reason why these novel drugs could be useful in cancer therapies, particularly in the case of leukemias and lymphomas.”

The more strategies being developed, the better for the thousands of patients diagnosed every year of blood malignancies. Perhaps, in the mid-term, turning leukemia cells into harmless types will be part of our arsenal against cancer.

 

Reference article:

Bueno-Costa A, Piñeyro D, García-Prieto CA, Ortiz-Barahona V, Martinez-Verbo L, Webster NA, Andrews B, Kol N, Avrahami C, Moshitch-Moshkovitz S, Rechavi G, Esteller M. Remodelling of the m⁶A RNA landscape in the conversion of acute lymphoblastic leukemia cells to macrophages. Leukemia, https://doi.org/10.1038/s41375-022-01621-1, 2022.

A team led by Dr. Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute, has improved the computational identification of potentially druggable gene amplifications in tumors, from epigenetic data. By using this new tool, scientists can have reliable information on the molecular data of a particular tumor, both at the genetics and epigenetics level, even from scarce samples.

Cancer cells exhibit a plethora of genetic and epigenetic alterations that are both the cause and the consequence of its deep dysregulation. Epigenetic abnormalities impair the proper function of genes, either increasing or decreasing its activity, while genetic alterations often imply mutations or gains and losses of entire genes or chromosome fragments. The latter, named Somatic Copy Number Alterations (SCNAs) have been associated with anticancer drug response: the higher the copy number amplification of a target gene, the higher its sensitivity to the targeted treatment.

Genetic and epigenetic profiling of a tumor can help define its prognosis and treatment options. However, it takes a large sample to do both analysis and this is not always available. The researchers’ team at the Josep Carreras Leukaemia Research Institute have improved a previous tool (conumee) to develop the new conumee-Kcn, able to improve the characterization of SCNAs up to a 20%, and distinguish between low gains, moderate amplifications and high amplifications.

The new methodology, published at the scientific journal Briefings in Bioinformatics, uses dynamic thresholding and tumor purity estimates over DNA-methylation array data to infer SCNAs with high accuracy, reaching a 100% specificity and 93.3% sensitivity in the preliminary experimental tests, using the gold standard fluorescence in situ hybridization (FISH) assay. Hence, with the same information used to profile the epigenetics signature of a tumor, they can estimate genetic copy number variations, a highly relevant clinical feature; two birds with one stone.

Though this estimation is not as good as when using the standard SNP arrays, a methodology specifically designed to SCNA analysis, it offers valuable information when facing limited samples and resampling is not possible or advised, like in lung cancers.

After the benchmarking, the researchers tested the reliability of conumee-Kcn on stored samples from Cancers of Unknown Primary (CUPs), a type of highly aggressive metastatic tumors with poor prognosis due to its unknown origin. Dr. Verónica Dávalos, lead co-author of the research, states that up to 15 potentially druggable targets were identified in those samples, opening the door to new treatment opportunities in the future for this dismal tumor type.

The capacity to treat CUPs, and any other cancer type, only by its genetic and epigenetic alterations, regardless of its origin, is a new approach to fight cancer in a tissue-agnostic manner. On this regard, the Cancer Epigenetics group at the Josep Carreras Leukaemia Research Institute is deepening its knowledge on the molecular features of CUPs to bring new treatment options to the clinician’s arsenal.