2026-08-05T09:54:36Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/165002024-11-29T09:36:55Zcom_20.500.12105_2052com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19608col_20.500.12105_16977
Repisalud
author
Lahera, Antonio
author
Vela-Martín, Laura
author
Fernandez-Navarro, Pablo L
author
Llamas, Pilar
author
López-Lorenzo, José L
author
Cornago, Javier
author
Santos, Javier
author
Fernández-Piqueras, José
author
Villa-Morales, María
funder
Ministerio de Economía y Competitividad (España)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Fundación Ramón Areces
funder
Comunidad de Madrid (España)
funder
Asociación Española Contra el Cáncer
funder
Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
funder
Banco Santander
funder
Centro de Biología Molecular Severo Ochoa
2023-09-26T09:17:35Z
2023-09-26T09:17:35Z
2024
Mol Carcinog. 2024 Jan;63(1):5-10.
10.1002/mc.23632
1098-2744
Molecular carcinogenesis
37712558
http://hdl.handle.net/20.500.12105/16500
T-cell acute lymphoblastic leukemia (T-ALL) arises from the malignant transformation of T-cell progenitors at various differentiation stages. Given that patients who relapse have a dismal prognosis, there is an urgent need to identify the molecular alterations that are present in such patients and promote leukemogenesis to implement personalized therapies with higher efficacy and fewer adverse effects. In the present manuscript, we identified the JAK3Q988P mutation in a T-ALL patient who did not achieve a durable response after the conventional treatment and whose tumor cells at relapse presented constitutive activation of the JAK/STAT pathway. Although JAK3Q988P has been previously identified in T-ALL patients from different studies, the functional consequences exerted by this mutation remain unexplored. Through the combination of different hematopoietic cellular models, we functionally characterize JAK3Q988P as an oncogenic mutation that contributes to leukemogenesis. Notably, JAK3Q988P not only promotes constitutive activation of the JAK/STAT pathway in the absence of cytokines and growth factors, as is the case for other JAK3 mutations that have been functionally characterized as oncogenic, but also functions independently of JAK1 and IL2RG, resulting in high oncogenic potential as well as resistance to ruxolitinib. Our results indicate that ruxolitinib may not be efficient for future patients bearing the JAK3Q988P mutation who instead may obtain greater benefits from treatments involving other pharmacological inhibitors such as tofacitinib.
eng
JAK/STAT
JAK3
T-ALL
Ruxolitinib
The JAK3Q988P mutation reveals oncogenic potential and resistance to ruxolitinib
research article
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