背景:尽管使用了靶向治疗方法,T细胞急性淋巴细胞白血病(T-ALL)仍然与并发症的高发生率和不良预后有关。Indisulam(也称为E7070),一种新发现的分子胶化合物,通过RBM39的快速降解,已证明在几种类型的癌症中具有更高的治疗效果。本研究旨在评估indusulam在T-ALL中的治疗潜力,阐明其潜在机制并探讨RBM39基因的作用。
方法:我们在体内和体外模型中验证了靛舒兰的抗癌作用。此外,使用shRNA构建RBM39敲低细胞系证实T-ALL细胞的恶性表型依赖于RBM39。通过RNA测序,我们确定了indusulam诱导的剪接异常,蛋白质组学分析有助于查明药物引起的蛋白质变化。这些发现的综合交叉分析有助于下游效应物的识别和随后对其功能作用的验证。
结果:印度舒兰对T-ALL有显著的抗肿瘤作用。它减弱细胞增殖,在T-ALL体内模型中促进细胞凋亡并干扰体外细胞周期进程,同时促进肿瘤缓解。这项研究提供了证据,表明RBM39的下调导致T-ALL细胞在体外和体内的增殖受限,表明RBM39是T-ALL治疗的潜在靶标。Indiusulam的功效归因于其诱导RBM39降解的能力,导致关键下游效应蛋白广泛的异常剪接和异常翻译,THOC1,最终导致蛋白质消耗。此外,DCAF15的存在被认为对indisulam的有效性至关重要,并且它的缺失否定了indusulam诱导所需功能改变的能力。
结论:我们的研究表明,靶向RBM39诱导肿瘤细胞凋亡,是治疗T-ALL的有效药物。通过indusulam靶向RBM39导致前mRNA的错误剪接,导致THOC1等关键效应器的丢失。
BACKGROUND: Despite the use of targeted therapeutic approaches, T-cell acute lymphoblastic leukemia (T-ALL) is still associated with a high incidence of complications and a poor prognosis. Indisulam (also known as E7070), a newly identified molecular glue compound, has demonstrated increased therapeutic efficacy in several types of cancer through the rapid degradation of RBM39. This study aimed to evaluate the therapeutic potential of indisulam in T-ALL, elucidate its underlying mechanisms and explore the role of the RBM39 gene.
METHODS: We verified the anticancer effects of indisulam in both in vivo and in vitro models. Additionally, the construction of RBM39-knockdown cell lines using shRNA confirmed that the malignant phenotype of T-ALL cells was dependent on RBM39. Through RNA sequencing, we identified indisulam-induced splicing anomalies, and proteomic analysis helped pinpoint protein changes caused by the drug. Comprehensive cross-analysis of these findings facilitated the identification of downstream effectors and subsequent validation of their functional roles.
RESULTS: Indisulam has significant antineoplastic effects on T-ALL. It attenuates cell proliferation, promotes apoptosis and interferes with cell cycle progression in vitro while facilitating tumor remission in T-ALL in vivo models. This investigation provides evidence that the downregulation of RBM39 results in the restricted proliferation of T-ALL cells both in vitro and in vivo, suggesting that RBM39 is a potential target for T-ALL treatment. Indisulam\'s efficacy is attributed to its ability to induce RBM39 degradation, causing widespread aberrant splicing and abnormal translation of the critical downstream effector protein, THOC1, ultimately leading to protein depletion. Moreover, the presence of DCAF15 is regarded as critical for the effectiveness of indisulam, and its absence negates the ability of indisulam to induce the desired functional alterations.
CONCLUSIONS: Our study revealed that indisulam, which targets RBM39 to induce tumor cell apoptosis, is an effective drug for treating T-ALL. Targeting RBM39 through indisulam leads to mis-splicing of pre-mRNAs, resulting in the loss of key effectors such as THOC1.