期刊
CANCER RESEARCH
卷 82, 期 6, 页码 1098-1109出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-3386
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资金
- FEDER MINECO [SAF201783061-R]
- Fundacion Ramon Areces
- Fundacion Sindrome de Wolf-Hirschhorn o 4p
- Banco de Santander
- EU COST Action LEGEND [CA16223]
- Instituto de Salud Carlos III [PI17/00167]
- Miguel Servet Grant [CPII19/00024]
- European Regional Development Fund (ERDF)/European Social Fund (ESF)
- American Lebanese Syrian Associated Charities (ALSAC)
- NCI [R01CA241452]
- FEDER
- MINECO/FEDER, UE [SAF201564420-R]
- MCIU/AEI/FEDER, UE [RTI2018-093314-B-I00, 9659122185-122185-4-21]
- Junta de Castilla y Leon [UIC017, CSI001U16, CSI234P18, CSI144P20]
- Fundacion Unoentrecienmil (CUNINA project)
- Fundacion Cientifica de la Asociacion Espanola contra el Cancer [PRYCO211305SANC]
- FSE-Conserjeria de Educacion de la Junta de Castilla y Leon [CSI067-18, CSI021-19]
- University of Salamanca
- ESF
- Ayuda para Contratos predoctorales para la formacion de doctores [PRE2019-088887]
This study demonstrates that early-life administration of the JAK1/2 inhibitor ruxolitinib significantly reduces the risk of B-ALL in mice. This finding presents a potential strategy for preventing the development of B-ALL.
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.
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