T-淋巴细胞急性淋巴细胞白血病(T-ALL)是一种侵袭性造血肿瘤，由T细胞前体的恶性转化引起。虽然激活NOTCH1突变是T-ALL的主导遗传驱动因素，但表观遗传失调在T-ALL的病理学中起着核心作用，并可在遗传突变的情况下或同时提供癌症发生的替代机制。组蛋白去甲基化酶酶KDM6A(UTX)也经常发生T-ALL患者的突变并发挥肿瘤抑制作用。但是，它的基因同源体KDM6B(JMJD3)从未发生过突变，并且可以显著过度表达，这表明它可能是维持该疾病所必需的。在这里，我们使用小鼠和人类T-ALL模型来展示，KDM6B对于T-ALL的发展和维持是必需的。使用NOTCH1增益功能逆转录模型，Kdm6b基因缺陷小鼠细胞无法传播T-ALL。通过CRISPR / Cas9失活人类T-ALL患者细胞中的KDM6B表明，KDM6B靶向细胞的竞争能力随着时间的推移显着降低。T-ALL细胞对KDM6B的依赖程度与NOTCH1突变的致癌强度成正比，因为KDM6B需要防止强烈的NOTCH1信号诱导的应激性凋亡。这些研究确定了KDM6B在维持NOTCH1驱动的T-ALL中发挥重要作用，并将KDM6B定位为这些患者的新型治疗靶点。©2023作者，独家授权Springer Nature有限公司。

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors. While activating NOTCH1 mutations are the dominant genetic drivers of T-ALL, epigenetic dysfunction plays a central role in the pathology of T-ALL and can provide alternative mechanisms to oncogenesis in lieu of or in combination with genetic mutations. The histone demethylase enzyme KDM6A (UTX) is also recurrently mutated in T-ALL patients and functions as a tumor suppressor. However, its gene paralog, KDM6B (JMJD3), is never mutated and can be significantly overexpressed, suggesting it may be necessary for sustaining the disease. Here, we used mouse and human T-ALL models to show that KDM6B is required for T-ALL development and maintenance. Using NOTCH1 gain-of-function retroviral models, mouse cells genetically deficient for Kdm6b were unable to propagate T-ALL. Inactivating KDM6B in human T-ALL patient cells by CRISPR/Cas9 showed KDM6B-targeted cells were significantly outcompeted over time. The dependence of T-ALL cells on KDM6B was proportional to the oncogenic strength of NOTCH1 mutation, with KDM6B required to prevent stress-induced apoptosis from strong NOTCH1 signaling. These studies identify a crucial role for KDM6B in sustaining NOTCH1-driven T-ALL and implicate KDM6B as a novel therapeutic target in these patients.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.