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Brazilian and Portuguese researchers found that an aggressive type of leukemia Acute lymphoid (ALL), the most common cancer in children, is caused by a mutation in the gene that produces a protein involved in immunity (IL-7R).
“Based on an animal model developed in Brazil, we observed that the continuous activation of the IL-7R protein function, even at physiological levels of its expression, triggers the exaggerated proliferation of leukocytes (white blood cells) of the lymphocyte family, giving rise to leukemia severe acute. The finding is important because, with a greater understanding at the molecular level of the disease and its genetic causes, it is possible to propose new treatments, especially for cases of recurrence or in which the conventional treatment does not work”, says José Andrés Yunes, researcher at the Centro Infantil Boldrini and author of the study.
The study, published in the journal Nature Communications, was carried out by researchers from the Centro Infantil Boldrini (Brazil) and the João Lobo Antunes Institute of Molecular Medicine (iMM), in Portugal. The discovery is the result of a research grant granted by FAPESP in partnership with the Portuguese Foundation for Science and Technology (FCT).
According to the research, the mutation in the IL-7R-producing gene, in addition to triggering leukemia, also stimulates new mutations in other genes – such as PAX5 and KRAS – that make the disease progress.
“The IL-7R mutation is not enough to give rise to leukemia. There are other genes that are also involved in the disease. For leukemia to occur, other mutations are needed, which collaborate with the IL-7R to interrupt the cell differentiation program and make the cells continue to proliferate in an exaggerated manner and survive”, he explains.
Acute lymphoid leukemia (ALL) is an exaggerated proliferation of B cells – progenitors of lymphocytes. Currently, conventional therapies such as chemotherapy are effective in up to 90% of cases. However, as they are difficult treatments, the average cure rate in Brazil is between 40% and 50%. In adults, therapeutic success is worse than in children, with 30% to 40% survival.
“The leukemia developed in mice resembles a subtype of the disease called “ph-like”, which is a more aggressive type of severe acute leukemia and affects both children and adults, but it is more frequent in adolescents and young adults,” says Yunes .
The researcher explains that the name is “ph-like” because this type of leukemia presents a pattern of gene expression typical of the so-called ALL ph+, which is a leukemia characterized by the presence of the Philadelphia chromosome (ph) resulting from the t(9;22) translocation ). Like ALL ph+, ALL ph-like have protein tyrosine kinase hyperactivation, which is what IL-7R ends up activating too.
In the study, the researchers produced two models of transgenic mice, but the one developed in Brazil was the one that proved to be the most efficient for carrying out research and understanding oncogenesis. “This experimental model can now be used in new studies on the disease”, says Yunes.
The researcher explains that, in general, cells tend to control the production of IL-7R in order to avoid the uncontrolled activation of the protein. “This is mainly due to the control at the transcription level, which is when the gene is transcribed into a messenger RNA”, he says.
Unlike other studies on genes related to the appearance and growth of tumors, the researchers developed a transgenic mouse model that simulated the mutation in the IL-7R gene without, however, altering its transcriptional control. “With this, we were able to keep the mutant IL-7R protein produced at the same stages of lymphocyte maturation and with the same intensity. Thus, the effect of the mutation can be assessed at normal physiological levels. It was a model that might not work as well as it actually did, but we chose to better mirror what happens in humans”, he explains.
After analyzing how the disease was activated in animals, the two teams performed genomic sequencing studies in leukemic cells to identify which other genes were altered. In Portugal, researchers performed the sequencing of pre-leukemic cells as well.
The researchers also performed analyzes on the exome – part of the genome where the protein-coding genes are located and, therefore, where there is a greater chance of disease-causing mutations. Finally, they analyzed all the data together.
“In Portugal, some drugs that inhibit the molecular effects of IL-7R were tested. Studies were carried out with panels of drugs that may, in the future, be tested in animals and then in humans until their effectiveness is proven. In any case, they are important findings, as they also allow us to propose the most suitable treatment for each patient based on the identification of these alterations”, he says.