2. Academic Validation
  3. Targeting RBM39 through indisulam induced mis-splicing of mRNA to exert anti-cancer effects in T-cell acute lymphoblastic leukemia

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.
Tongting Ji # 1,  Yang Yang # 2,  Juanjuan Yu # 1,  Hongli Yin # 2,  Xinran Chu # 3,  Pengju Yang 1,  Ling Xu 1 4,  Xiaodong Wang 5,  Shaoyan Hu 3,  Yizhen Li 2,  Xiaochen Wu 1,  Wengyuan Liu 6,  Bi Zhou 1 7,  Wenjuan Wang 8,  Shuqi Zhang 1 9,  Wei Cheng 1 9,  Yanling Chen 1,  Lei Shi 10,  Zhiheng Li 2,  Ran Zhuo 1,  Yongping Zhang 3,  Yanfang Tao 2,  Di Wu 2,  Xiaolu Li 2,  Zimu Zhang 2,  Jun-Jie Fan 3,  Jian Pan 11,  Jun Lu 12
Affiliations

Affiliations

  • 1 Children's Hospital of Soochow University, Suzhou, 215003, China.
  • 2 Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
  • 3 Department of Hematology, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, Jiangsu, 215003, China.
  • 4 Department of Pediatric, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China.
  • 5 Department of Orthopaedics, Children's Hospital of Soochow University, Suzhou, 215003, China.
  • 6 Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei City, 230601, China.
  • 7 Department of Pediatric, Suzhou Hospital of AnHui Medical University, Suzhou, 234000, China.
  • 8 Department of Pharmacy, Children's Hospital of Soochow University, Suzhou, Jiangsu, 215025, China.
  • 9 Department of Pediatrics, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241002, China.
  • 10 Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
  • 11 Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China. panjian2008@163.com.
  • 12 Department of Hematology, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, Jiangsu, 215003, China. drlujun_sz@163.com.
  • # Contributed equally.
PMID: 39044280 DOI: 10.1186/s13046-024-03130-8
Abstract

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.

Conclusion: 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.

Keywords

Indisulam; RBM39; RNA splicing; T-ALL; THOC1.

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