An international study in which scientists from the Higher Council for Scientific Research (CSIC) have participated has found a strategy to prevent the development of childhood leukemia that has demonstrated its effectiveness in tests with mice. Specifically, the researchers have described a way to prevent preleukemic cells from leading to B-cell lymphoblastic leukemia. The results of the work have been published in Cancer Research, of the American Association for Cancer Research.
B-cell acute lymphoblastic leukemia is the most common form of childhood cancer. 5% of children who are born healthy have genetic alterations in B cells –located in the PAX5 gene– that predispose them to developing this disease. Having this genetic predisposition does not mean that you will suffer from leukemia, but rather that other secondary mutations have to occur.
Ruxolitinib prevents secondary mutations and specifically kills preleukemic B cells without affecting normal B cells
These secondary mutations are generated in the JAK/STAT cell signaling pathway and could be caused by immune stress, a reaction that can be triggered by certain infections. The new research has been based on a preventive approach to prevent these secondary mutations from occurring, and thus, even in the event of a genetic predisposition, leukemia would not arise.
If these secondary mutations are stopped, it would be possible to block the development of leukemia, even though the individual’s cells have the initial mutation of the PAX5 gene. It is more difficult, however, to correct the initial mutations with which the individual is born, since these are produced in the eggs or sperm of the parents.
Prevent leukemia by avoiding secondary genetic mutations
“In this work we have given a drug (ruxolitinib) to mice with the mutated PAX5 gene, and at the time of exposure to the infection that generates immune stress, in order to eradicate preleukemic cells”, explains researcher Isidro Sánchez-GarcÃa , a researcher at the Cancer Research Center (CISC-University of Salamanca), who has participated in the study. This drug inhibits the JAK1/2 signaling pathway, prevents secondary mutations, and specifically kills preleukemic B cells (with the PAX5 gene mutation) without affecting normal B cells.
“The precondition for the development of the disease is that the PAX5 gene is mutated, but its progression does not occur until the immune stress facilitates the appearance of mutations in the JAK/STAT signaling pathway”, specifies Sánchez- Garcia. “Therefore, childhood leukemia could be prevented if these secondary mutations were avoided,” she adds.
This study has provided the first in vivo evidence that this strategy can prevent the development of B-cell acute lymphoblastic leukemia. Only one of the 29 mice treated with the drug ruxolitinib went on to develop the disease, while of the 34 mice exposed to the infection and those who did not receive ruxolitinib treatment, eight developed it.
This preventive method could be applied to other cases of genetic susceptibility to childhood leukemia in which the secondary mutations present in the leukemic stages guide the identification of vulnerabilities within the population of preleukemic B cells. The finding also highlights the importance of further investigating specific approaches aimed at eliminating preleukemic B cells as a means of preventing the development of B-cell acute lymphoblastic leukemia.
The work has been carried out by researchers from the Cancer Research Center (CIC-IBMCC, joint center of the University of Salamanca-CSIC) in close collaboration with researchers from St. Jude Children’s Research Hospital (USA). and Novartis Institutes for BioMedical Research (Switzerland), and the project has had the support of the Unoentrecienmil Foundation through the Cunina project.
Source: Higher Council for Scientific Research (CSIC)
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