The JAK3Q988P mutation reveals oncogenic potential and resistance to ruxolitinib
Entity
UAM. Departamento de BiologíaPublisher
WileyDate
2023-09-15Citation
10.1002/mc.23632
Molecular Carcinogenesis (2023): 1-6
ISSN
0899-1987 (print); 1098-2744 (online)DOI
10.1002/mc.23632Funded by
This work was supported in part by funds from Ministerio de Economía y Competitividad (SAF2015‐70561‐R; MINECO/ FEDER, EU to J.F.‐P. and M.V.‐M.); Ministerio de Ciencia, Innovación y Universidades (RTI2018‐093330‐B‐I00; MCIU/FEDER, EU to J.F.‐P. and J.S.); Fundación Ramón Areces (CIVP19S7917 to J.F.‐P.); Comunidad de Madrid (B2017/BMD‐3778; LINFOMAS‐CM to J.F.‐P.); Asociación Española Contra el Cáncer (AECC, 2018; PROYE18054PIRI to J.F.‐P.); and Instituto de Investigación Sanitaria Fundación Jiménez Díaz to J.F.‐P.; institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSO are also acknowledgedProject
Gobierno de España. SAF2015‐70561‐R; Gobierno de España. RTI2018‐093330‐B‐I00Editor's Version
https://doi.org/10.1002/mc.23632Subjects
JAK/STAT; JAK3; Ruxolitinib; T-ALL; Biología y Biomedicina / BiologíaRights
© 2023 The AuthorsAbstract
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
Files in this item
Google Scholar:Lahera Alonso, Antonio
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Vela Martín, Laura
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Fernández Navarro, Pablo
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Llamas Sillero, Pilar
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López Lorenzo, José L.
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Cornago, Javier
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Santos, Javier
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Fernández Piqueras, José
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Villa Morales, María del Consuelo
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