2. Academic Validation
  3. The RBM39 degrader indisulam inhibits acute megakaryoblastic leukemia by altering the alternative splicing of ZMYND8

The RBM39 degrader indisulam inhibits acute megakaryoblastic leukemia by altering the alternative splicing of ZMYND8

  • Cell Biosci. 2025 Apr 13;15(1):46. doi: 10.1186/s13578-025-01380-3.
Ying Yang # 1,  Zhiheng Li # 2 3 4,  Yang Yang # 2,  Peifang Xiao # 3 4,  Zhixu He 1,  Zimu Zhang 2,  Yizhen Li 3 4,  Lei Shi 5,  Xiaodong Wang 6,  Yanfang Tao 2,  Junjie Fan 3,  Fenli Zhang 1,  Chunxia Yang 1,  Fahua Yao 7,  Tongting Ji 8,  Yongping Zhang 3 4,  Bi Zhou 8 9,  Juanjuan Yu 8,  Ailian Guo 3 4,  Zhongling Wei 3 4,  Wanyan Jiao 8 10,  Yumeng Wu 8 11,  Yan Li 8 12,  Di Wu 2,  Yijun Wu 8,  Li Gao 3 4,  Yixin Hu 3 4,  Jian Pan 13 14,  Shaoyan Hu 15 16,  Xiaoyan Yang 17
Affiliations

Affiliations

  • 1 Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Guiyang, 550001, 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, 215003, China.
  • 4 Jiangsu Pediatric Hematology and Oncology Center, Suzhou, 215003, China.
  • 5 Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
  • 6 Department of Orthopaedics, Children's Hospital of Soochow University, Suzhou, 215003, China.
  • 7 Department of Pediatrics, Guizhou Hospital, Shanghai Children's Medical Center, Guiyang, 550004, China.
  • 8 Children's Hospital of Soochow University, Suzhou, 215003, China.
  • 9 Department of Pediatrics, Suzhou Hospital Affiliated to Anhui Medical University, Suzhou Municipal Hospital of Anhui Province, Suzhou, 234000, China.
  • 10 Department of Pediatric, Yancheng Third People's Hospital, Yancheng, 224000, China.
  • 11 Department of Pediatric, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China.
  • 12 Department of Pediatric, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China.
  • 13 Institute of Pediatric Research, Children's Hospital of Soochow University, No. 92 Zhongnan Street, SIP, Suzhou, 215003, China. panjian2008@163.com.
  • 14 Jiangsu Pediatric Hematology and Oncology Center, Suzhou, 215003, China. panjian2008@163.com.
  • 15 Department of Hematology, Children's Hospital of Soochow University, No. 92 Zhongnan Street, SIP, Suzhou, 215003, China. hsy139@126.com.
  • 16 Jiangsu Pediatric Hematology and Oncology Center, Suzhou, 215003, China. hsy139@126.com.
  • 17 Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Guiyang, 550001, China. 469389553@qq.com.
  • # Contributed equally.
PMID: 40223119 DOI: 10.1186/s13578-025-01380-3
Abstract

Background: Acute megakaryoblastic leukemia (AMKL) is a rare hematological malignancy in adults but children. Alternative splicing (AS) has been shown to affect hematological Cancer progression, making splicing factors promising targets. Our research aims to investigate the efficacy of the molecular glue degrader indisulam, which targets the splicing factor RNA binding motif protein 39 (RBM39) in AMKL models.

Results: Public drug sensitivity data analysis revealed that AMKL cell lines exhibited the highest sensitivity to indisulam compared with Other tumor types. Then we confirmed that RBM39 depletion by indisulam treatment induced AMKL cell cycle arrest and Apoptosis. In AMKL mouse model, indisulam treatment significantly reduced the leukemic burden and prolonged the lifetime of AMKL mice. Mechanically, integration of transcriptomic and proteomic analyses revealed that indisulam-mediated RBM39 degradation resulted in AS of the transcription factor zinc finger MYND-type containing 8 (ZMYND8), an AMKL cell growth regulator. Finally, the effectiveness of indisulam depended on DDB1- and Cul4- Associated Factor 15 (DCAF15) expression because knockout of DCAF15 rescued the indisulam-induced RBM39 degradation and mis-splicing of ZMYND8.

Conclusion: Indisulam is a promising therapeutic candidate for AMKL and the RBM39-mediated ZMYND8 splicing plays an important role in promoting the development of AMKL.

Keywords

Acute megakaryoblastic leukemia; Alternative splicing; Indisulam; RBM39; ZMYND8.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z