2026-08-05T09:54:35Zhttps://repisalud.isciii.es/rest/oai/request

oai: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

00925njm 22002777a 4500 dc 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 author 2024 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. 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 JAK/STAT JAK3 T-ALL Ruxolitinib The JAK3Q988P mutation reveals oncogenic potential and resistance to ruxolitinib