BRD4 PROTAC degrader MZ1 exhibits anti-B-cell acute lymphoblastic leukemia effects via targeting CCND3

Li Ma; Jianwei Wang; Yang Yang; Jun Lu; Jing Ling; Xinran Chu; Zimu Zhang; Yanfang Tao; Xiaolu Li; Yuanyuan Tian; Zhiheng Li; Yongping Zhang; Xu Sang; Lihui Lu; Xiaomei Wan; Kunlong Zhang; Yanling Chen; Juanjuan Yu; Ran Zhuo; Shuiyan Wu; Jian Pan; Xiuxia Zhou; Yixin Hu; Shaoyan Hu

doi:10.1080/16078454.2023.2247253

Hematology (Dec 2023)

BRD4 PROTAC degrader MZ1 exhibits anti-B-cell acute lymphoblastic leukemia effects via targeting CCND3

Li Ma,
Jianwei Wang,
Yang Yang,
Jun Lu,
Jing Ling,
Xinran Chu,
Zimu Zhang,
Yanfang Tao,
Xiaolu Li,
Yuanyuan Tian,
Zhiheng Li,
Yongping Zhang,
Xu Sang,
Lihui Lu,
Xiaomei Wan,
Kunlong Zhang,
Yanling Chen,
Juanjuan Yu,
Ran Zhuo,
Shuiyan Wu,
Jian Pan,
Xiuxia Zhou,
Yixin Hu,
Shaoyan Hu

Affiliations

Li Ma: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Jianwei Wang: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Yang Yang: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Jun Lu: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Jing Ling: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Xinran Chu: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Zimu Zhang: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Yanfang Tao: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Xiaolu Li: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Yuanyuan Tian: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Zhiheng Li: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Yongping Zhang: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Xu Sang: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Lihui Lu: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Xiaomei Wan: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Kunlong Zhang: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Yanling Chen: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Juanjuan Yu: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Ran Zhuo: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Shuiyan Wu: Intensive Care Unit, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Jian Pan: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Xiuxia Zhou: Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Yixin Hu: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China
Shaoyan Hu: Department of Hematology, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China

DOI: https://doi.org/10.1080/16078454.2023.2247253
Journal volume & issue: Vol. 28, no. 1

Abstract

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ABSTRACTIntroduction B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent malignant tumor affecting children. While the majority of B-ALL patients (90%) experience successful recovery, early relapse cases of B-ALL continue to exhibit high mortality rates. MZ1, a novel inhibitor of Bromodomains and extra-terminal (BET) proteins, has demonstrated potent antitumor activity against hematological malignancies. The objective of this study was to examine the role and therapeutic potential of MZ1 in the treatment of B-ALL.Methods In order to ascertain the fundamental mechanism of MZ1, a sequence of in vitro assays was conducted on B-ALL cell lines, encompassing Cell Counting Kit 8 (CCK8) assay, Propidium iodide (PI) staining, and Annexin V/PI staining. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to examine protein and mRNA expression levels. Transcriptomic RNA sequencing (RNA-seq) was utilized to screen the target genes of MZ1, and lentiviral transfection was employed to establish stably-expressing/knockdown cell lines.Results MZ1 has been observed to induce the degradation of Bromodomain Containing 4 (BRD4), Bromodomain Containing 3 (BRD3), and Bromodomain Containing 2 (BRD2) in B-ALL cell strains, leading to inhibited cell growth and induction of cell apoptosis and cycle arrest in vitro. These findings suggest that MZ1 exhibits cytotoxic effects on two distinct molecular subtypes of B-ALL, namely 697 (TCF3/PBX1) and RS4;11 (MLL-AF4) B-ALL cell lines. Additionally, RNA-sequencing analysis revealed that MZ1 significantly downregulated the expression of Cyclin D3 (CCND3) gene in B-ALL cell lines, which in turn promoted cell apoptosis, blocked cell cycle, and caused cell proliferation inhibition.Conclusion Our results suggest that MZ1 has potential anti-B-ALL effects and might be a novel therapeutic target.

Published in Hematology

ISSN: 1024-5332 (Print); 1607-8454 (Online)
Publisher: Taylor & Francis Group
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the blood and blood-forming organs
Website: https://www.tandfonline.com/journals/yhem

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