T-细胞急性淋巴细胞白血病（T-ALL）是指T细胞前体在不同分化阶段发生恶性转化。由于复发患者的预后很差，迫切需要确定这些患者中存在的分子改变和促进白血病发展的因素，以实施个体化疗法，提高疗效，减少副作用。本文中，我们鉴定了一个T-ALL患者的JAK3Q988P突变，该患者在经过常规治疗后未能取得持久的疗效，复发时肿瘤细胞呈现出JAK/STAT通路的持续激活。尽管JAK3Q988P已在不同研究中发现了T-ALL患者中，但这种突变所带来的功能后果仍未被探索。通过结合不同造血细胞模型，我们对JAK3Q988P进行了功能性的鉴定，证明其是一个致癌突变，有助于白血病发展。值得注意的是，JAK3Q988P不仅在缺乏细胞因子和生长因子时促使JAK/STAT通路的持续激活，这与已经被鉴定为致癌的其他JAK3突变的情况相似，而且独立于JAK1和IL2RG的功能，导致其具有较高的致癌潜力并对如鲁索利替尼表现出耐药性。我们的结果表明，对于未来携带JAK3Q988P突变的患者，鲁索利替尼可能不是一种高效的治疗药物，相反，这些患者可能会从使用其他药物抑制剂（例如托法替尼布）的治疗中获得更大的益处。© 2023 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.

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.© 2023 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.