2. Academic Validation
  3. BRD4 PROTAC degrader MZ1 exhibits anti-B-cell acute lymphoblastic leukemia effects via targeting CCND3

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

  • Hematology. 2023 Dec;28(1):2247253. doi: 10.1080/16078454.2023.2247253.
Li Ma 1 2,  Jianwei Wang 3,  Yang Yang 3,  Jun Lu 1,  Jing Ling 1,  Xinran Chu 1,  Zimu Zhang 3,  Yanfang Tao 3,  Xiaolu Li 3,  Yuanyuan Tian 1 3,  Zhiheng Li 3,  Yongping Zhang 1,  Xu Sang 1,  Lihui Lu 1,  Xiaomei Wan 1,  Kunlong Zhang 1,  Yanling Chen 3,  Juanjuan Yu 3,  Ran Zhuo 3,  Shuiyan Wu 4,  Jian Pan 3,  Xiuxia Zhou 3,  Yixin Hu 1,  Shaoyan Hu 1
Affiliations

Affiliations

  • 1 Department of Hematology, Children's Hospital of Soochow University, Suzhou, People's Republic of China.
  • 2 Department of Pediatrics, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, People's Republic of China.
  • 3 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, People's Republic of China.
  • 4 Intensive Care Unit, Children's Hospital of Soochow University, Suzhou, People's Republic of China.
PMID: 37594294 DOI: 10.1080/16078454.2023.2247253
Abstract

Introduction: 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.

Keywords

B-cell acute lymphoblastic leukemia; BET inhibitor; BRD4; CCND3; MZ1.

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