Abstract：
T-cell acute lymphoblastic leukaemia (T-ALL) is a highly aggressive and heterogeneous lymphoid malignancy with poor prognosis in adult patients. Aberrant activation of the NOTCH1 signalling pathway is involved in the pathogenesis of over 60% of T-ALL cases. Ubiquitin-specific protease 28 (USP28) is a deubiquitinase known to regulate the stability of NOTCH1. Here, we report that genetic depletion of USP28 or using CT1113, a potent small molecule targeting USP28, can strongly destabilize NOTCH1 and inhibit the growth of T-ALL cells. Moreover, we show that USP28 also regulates the stability of sterol regulatory element binding protein 1 (SREBP1), which has been reported to mediate increased lipogenesis in tumour cells. As the most critical transcription factor involved in regulating lipogenesis, SREBP1 plays an important role in the metabolism of T-ALL. Therefore, USP28 may be a potential therapeutic target, and CT1113 may be a promising novel drug for T-ALL with or without mutant NOTCH1.
摘要：
T细胞急性淋巴细胞白血病（T-ALL）是一种高度侵袭性和异质性的淋巴恶性肿瘤，在成年患者中预后不良。超过60%的T-ALL病例的发病机制涉及NOTCH1信号通路的异常激活。泛素特异性蛋白酶28（USP28）是一种去泛素酶，已知可调节NOTCH1的稳定性。这里,我们报道,USP28的基因耗竭或使用CT1113,一种靶向USP28的有效小分子,可强烈破坏NOTCH1的稳定性并抑制T-ALL细胞的生长.此外，我们显示USP28还调节固醇调节元件结合蛋白1（SREBP1）的稳定性，据报道，它可以介导肿瘤细胞中脂肪生成的增加。作为参与调节脂肪生成的最关键的转录因子,SREBP1在T-ALL的代谢中起重要作用。因此,USP28可能是一个潜在的治疗靶点，和CT1113可能是治疗T-ALL的有前途的新型药物，有或没有突变NOTCH1。
