Children's Hospital of Soochow University, Suzhou, 215003, China.
Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
J Exp Clin Cancer Res. 2024 Jul 24;43(1):205. doi: 10.1186/s13046-024-03130-8.
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.
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.
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.
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.
尽管采用了靶向治疗方法，T 细胞急性淋巴细胞白血病（T-ALL）仍然与高并发症发生率和预后不良相关。Indisulam（也称为 E7070）是一种新鉴定的分子胶化合物，通过快速降解 RBM39，在几种类型的癌症中显示出增强的治疗效果。本研究旨在评估 indisulam 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。
我们在体内和体外模型中验证了 indisulam 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，我们鉴定了 indisulam 诱导的剪接异常，蛋白质组学分析有助于确定药物引起的蛋白质变化。对这些发现进行综合交叉分析有助于确定下游效应物，并随后验证其功能作用。
Indisulam 对 T-ALL 具有显著的抗肿瘤作用。它在体外抑制细胞增殖、促进细胞凋亡和干扰细胞周期进程，同时促进 T-ALL 体内模型中的肿瘤缓解。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到限制，表明 RBM39 是 T-ALL 治疗的潜在靶点。Indisulam 的疗效归因于它诱导 RBM39 降解的能力，导致广泛的异常剪接和关键下游效应蛋白 THOC1 的异常翻译，最终导致蛋白质耗竭。此外，DCAF15 的存在被认为对 indisulam 的有效性至关重要，其缺失否定了 indisulam 诱导所需功能改变的能力。
我们的研究表明，通过靶向 RBM39 诱导肿瘤细胞凋亡的 indisulam 是治疗 T-ALL 的有效药物。通过 indisulam 靶向 RBM39 导致 pre-mRNAs 的错误剪接，导致关键效应物如 THOC1 的丢失。
