The role of Pax5 in B-cell acute lymphoblastic leukemia
Belén María Ruiz Corzo
Centro de Investigación del Cáncer (CSIC, USAL, FICUS)
Precursor B-cell acute lymphoblastic leukemia (B-ALL) results from an accumulation of pre-B cells and pro-B cells in the bone marrow due to a blockage in the differentiation process toward mature B cells. B-ALL accounts for approximately 85% of childhood ALL cases. Although current therapies achieve cure rates of nearly 90%, B-cell ALL remains one of the leading causes of pediatric mortality due to high relapse rates and long-term side effects. It is estimated that at least 5% of newborns have some of these genetic alterations, although only 1% of them eventually develop the disease. This indicates that the presence of a primary genetic alteration is not the sole determining factor in the genesis of B-ALL; rather, it is believed that progression to the disease requires a second event, induced by immune stress associated with environmental factors, which promotes the acquisition of secondary genetic mutations or alterations, as would be the case with exposure to infections. In these cases, mouse models that are heterozygous for the Pax5 gene (Pax5 +/- ) and exposed to common pathogens mediate the development of B-ALL through innate immune mechanisms, which cause inflammation and consequent DNA damage. However, these inflammatory signals do not increase the risk of B-ALL development in mice that do not have any mutations in the Pax5 gene. Therefore, we used mouse models to elucidate the role of Pax5 in the response to DNA damage. However, there are some cases in which B-ALL develops in the absence of immune stress, such as in B-ALLs with deletions on the short arm of chromosome 9 (9p). In such situations, the loss of PAX5 is associated with the development of leukemia without the need for exposure to environmental factors. To understand how these B-ALLs develop, we use mouse models heterozygous for genes located in this 9p region.