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Marta animal gallego4/27/2023 ![]() ![]() Several recent studies have provided strong evidence confirming the hypothesis that exposure to infections can be a driver of clonal evolution of preleukemic cells toward overt leukemia ( 5–11). This clinically silent preleukemic condition is estimated to be present in more than 5% of the healthy childhood population and does not evolve to disease in the vast majority of cases (4). For many types of childhood B-ALL, there exists a latent preleukemic phase in which the initiating somatic or germline genetic event is present, but leukemia does not develop. ![]() These findings provide the first in vivo evidence for a potential strategy to prevent B-ALL development.ī-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer and greatest cause of cancer-related death in children ( 1–3). Ruxolitinib treatment preferentially targeted Pax5 +/− versus wild-type B-cell progenitors and exerted unique effects on the Pax5 +/− B-cell progenitor transcriptional program. Here we show in Pax5 +/− mice that transient, early-life administration of clinically relevant doses of ruxolitinib, a JAK1/2 inhibitor, significantly mitigates the risk of B-ALL following exposure to infection 1 of 29 animals treated with ruxolitinib developed B-ALL versus 8 of 34 untreated mice. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge.
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