Casado-García, Ana, Isidro-Hernández, Marta , Oak, Ninad, Mayado, Andrea , Mann-Ran, Christine, Raboso-Gallego, Javier , Alemán-Artega, Silvia , Buhles, Alexandra, Sterker, Dario, Blanco, Oscar, Orfao, Alberto, Alonso-López, Diego, De Las Rivas, Javier, Riesco, Susana, Prieto-Matos, Pablo, Criado, Francisco Javier García, Cenador, María Begoña García, Radimerski, Thomas, Ramírez-Orellana, Manuel, Cobaleda, César, Yang, Jun J, Vicente-Dueñas, Carolina, Weiss, Andreas, Nichols, Kim E and Sánchez-García, Isidro (2022) Transient JAK/STAT pathway inhibition prevents natural occurring B-ALL development in genetically predisposed Pax5+/- mice. Cancer research, Epub a (canres). ISSN 1538-7445; 0008-5472

Abstract

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. Preclinical 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.

Item Type:	Article
Date Deposited:	23 Mar 2022 00:45
Last Modified:	23 Mar 2022 00:45
URI:	https://oak.novartis.com/id/eprint/45299