CLL

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.

Tongting Ji and the team aimed to evaluate the therapeutic potential of indisulam in T-ALL, elucidate its underlying mechanisms, and explore the role of the RBM39 gene.

They performed an inclusive analysis of the anticancer effects of indisulam using both in vivo and in vitro models. The construction of RBM39-knockdown cell lines with shRNA confirmed that the malignant phenotype of T-ALL cells relied on RBM39.

RNA sequencing revealed indisulam-induced splicing anomalies, while proteomic analysis identified protein changes induced by the drug. Comprehensive cross-analysis of these results, including patient samples, facilitated the identification and validation of downstream effectors and their functional roles.

About indisulam’s effects, significant antineoplastic activity was observed in 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 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.

The study concluded that indisulam, by targeting RBM39 to induce tumor cell apoptosis, is an effective drug for treating T-ALL. Targeting RBM39 through indisulam leads to the mis-splicing of pre-mRNAs, resulting in the loss of key effectors such as THOC1.

This study was funded by the National Key R&D Program of China (2022YFC2502700); National Natural Science Foundation (82072767, 82141110, 82203442, 82373414, 82172840, 82300182); Natural Science Foundation of Jiangsu Province (BK20220047); Jiangsu province’s science and technology support program (Social Development) project (BE2021657, BE2021654, BE2022732); Medical Research Project of Jiangsu Provincial Health and Family Planning Commission (Key Project ZD2021006); Suzhou Health Talent Training Project (GSWS2020047, GSWS2021028, GSWS2022062, GSWS2023048); the Science and Technology Development Project of Suzhou City (SKJY2021109, SKJY2021111, SKJY2021112, SKY2022170, SKY2022175, SKY2023192) and Jiangsu Provincial Health Commission Scientific Research Project (Z2022031, ZD2022056, M2022102, H2023106) and National Outstanding Youth Cultivation Program Project (YYJQ004).

Source: https://pubmed.ncbi.nlm.nih.gov/39044280/

Ji T, Yang Y, Yu J, et al. (2024). “Targeting RBM39 through indisulam induced mis-splicing of mRNA to exert anti-cancer effects in T-cell acute lymphoblastic leukemia.” J Exp Clin Cancer Res. 2024 Jul 24;43(1):205. doi: 10.1186/s13046-024-03130-8. PMID: 39044280; PMCID: PMC11267830.