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Titre
Transient inhibition of the JAK/STAT pathway prevents B-ALL development in genetically predisposed mice
Autor(es)
Sujet
Acute lymphoblastic-leukemia
Somatic point mutations
Incb018424 phosphate
Infection exposure
Cancer
Clasificación UNESCO
3201.01 Oncología
Fecha de publicación
2022
Éditeur
American Association for Cancer Research
Citación
Casado-García, A., Isidro-Hernández, M., Oak, N., Mayado, A., Mann-Ran, C., Raboso-Gallego, J., Alemán-Arteaga, S., Buhles, A., Sterker, D., Sánchez, E. G., Martínez-Cano, J., Blanco, O., Orfao, A., Alonso-López, D., De Las Rivas, J., Riesco, S., Prieto-Matos, P., González-Murillo, Á., García Criado, F. J., … Sánchez-García, I. (2022). Transient Inhibition of the JAK/STAT Pathway Prevents B-ALL Development in Genetically Predisposed Mice. Cancer Research, 82(6), 1098-1109. https://doi.org/10.1158/0008-5472.CAN-21-3386
Resumen
[EN]Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Predinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. 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. 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 strategy to prevent B-ALL development.
Significance: JAK/STAT inhibition suppresses tumorigenesis in a B-ALL-susceptible mouse model, presenting a novel approach to prevent B-ALL onset.
URI
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-21-3386
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