Transient JAK/STAT pathway inhibition prevents B-ALL development in genetically predisposed mice
Ana Casado García
Centro de Investigación del Cáncer (CIC-IBMCC), Salamanca
Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. In humans and mice, heterozygous germline alterations in the PAX5 gene can lead to B-ALL through the accumulation of secondary mutations affecting the JAK/STAT pathway. Preclinical studies have shown that this malignant transformation only occurs under an immune stress such as exposure to infectious pathogens. Here we show that transient treatment of Pax5+/- mice, early in life with clinically-relevant doses of ruxolitinib, a JAK1/2 inhibitor, can significantly mitigate 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). Ruxolitinib treatment preferentially targeted Pax5+/- versus wild-type B-cell progenitors and exerted unique effects on the Pax5+/- B-cell progenitor transcriptional program. These findings provide the first in vivo evidence for a potential preventive strategy for B-ALL development.