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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 JAK3<jats:sup>Q988P<\/jats:sup> mutation in a T\u2010ALL 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 JAK3<jats:sup>Q988P<\/jats:sup> has been previously identified in T\u2010ALL patients from different studies, the functional consequences exerted by this mutation remain unexplored. Through the combination of different hematopoietic cellular models, we functionally characterize JAK3<jats:sup>Q988P<\/jats:sup> as an oncogenic mutation that contributes to leukemogenesis. Notably, JAK3<jats:sup>Q988P<\/jats:sup> not only promotes constitutive activation of the JAK\/STAT pathway in the absence of cytokines and growth factors, as is the case for other <jats:italic>JAK3<\/jats:italic> 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 JAK3<jats:sup>Q988P<\/jats:sup> mutation who instead may obtain greater benefits from treatments involving other pharmacological inhibitors such as tofacitinib.<\/jats:p>","DOI":"10.1002\/mc.23632","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T11:34:59Z","timestamp":1694777699000},"page":"5-10","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The JAK3<sup>Q988P<\/sup> mutation reveals oncogenic potential and resistance to ruxolitinib"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8899-1376","authenticated-orcid":false,"given":"Antonio","family":"Lahera","sequence":"first","affiliation":[{"name":"Department of Biology Universidad Aut\u00f3noma de Madrid Madrid Spain"},{"name":"Department of Genome Dynamics and Function Centro de Biolog\u00eda Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Cient\u00edficas\u2010Universidad Aut\u00f3noma de Madrid (CSIC\u2010UAM) Madrid Spain"},{"name":"Division of Genetics and Genomics IIS Fundaci\u00f3n Jim\u00e9nez D\u00edaz Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Vela\u2010Mart\u00edn","sequence":"additional","affiliation":[{"name":"Department of Biology Universidad Aut\u00f3noma de Madrid Madrid Spain"},{"name":"Department of Genome Dynamics and Function Centro de Biolog\u00eda Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Cient\u00edficas\u2010Universidad Aut\u00f3noma de Madrid (CSIC\u2010UAM) Madrid Spain"},{"name":"Division of Genetics and Genomics IIS Fundaci\u00f3n Jim\u00e9nez D\u00edaz Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Fern\u00e1ndez\u2010Navarro","sequence":"additional","affiliation":[{"name":"Division of Cancer and 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