CSIC team demonstrates a strategy to prevent the development of childhood leukemia in mice

Cancer Research Center study describes pathway to prevent preleukemic cells from leading to B-cell lymphoblastic leukemia

10-Feb-2022 - Spain

An international team with researchers from the Spanish National Research Council (CSIC) has demonstrated for the first time in mice a novel strategy that prevents the development of childhood leukemia, or B-cell acute lymphoblastic leukemia. The results are published in Cancer Research.

B-cell acute lymphoblastic leukemia is the most common form of childhood cancer. From birth, 5% of healthy children have genetic alterations in their B cells that predispose them to develop it. These alterations are located in the PAX5 gene.

But this genetic predisposition alone does not trigger the disease. In addition to this initial gene alteration, other secondary mutations must occur for leukemia to develop. These secondary mutations occur in the JAK/STAT cell signaling pathway and could be caused by immune stress, a reaction that could be triggered by certain infections.

This study has used a preventive approach to target and prevent these secondary mutations, so that even if there is a genetic predisposition, leukemia would not arise. Thus, if these secondary mutations can be stopped, the development of leukemia could be blocked even if the cells contain the initial mutation of the PAX5 gene. (The initial mutations are more complex to "correct" since they occur in the eggs or sperm of the parents).

"In this work we have provided 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 the preleukemic cells," explains researcher Isidro Sánchez-García, from the Cancer Research Center (CISC-University of Salamanca), who has worked on the study. The drug inhibits the JAK1/2 signaling pathway, prevents secondary mutations and specifically eliminates 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 disease progression does not occur until immune stress facilitates the appearance of mutations in the JAK/STAT signaling pathway," Sánchez-García explains. "Therefore, childhood leukemia could be prevented if the appearance of these secondary mutations could be avoided," he adds.

This study has provided the first in vivo evidence that this strategy is capable of preventing the development of B-cell acute lymphoblastic leukemia. Specifically, of 29 mice treated with the drug ruxolitinib, only one developed the disease. However, of the 34 mice exposed to infection but not receiving ruxolitinib treatment, eight developed it.

This preventive approach could be applied to other cases of genetic susceptibility to childhood leukemia in which secondary mutations present in the leukemic stages guide the identification of vulnerabilities within the preleukemic B-cell population. Furthermore, this finding supports further investigation of specific approaches aimed at eliminating preleukemic B cells as a means of preventing the onset of B-cell acute lymphoblastic leukemia.

Note: This article has been translated using a computer system without human intervention. LUMITOS offers these automatic translations to present a wider range of current news. Since this article has been translated with automatic translation, it is possible that it contains errors in vocabulary, syntax or grammar. The original article in Spanish can be found here.

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