BRD4 PROTAC degrader MZ1 exerts anticancer effects in acute myeloid leukemia by targeting c-Myc and ANP32B genes.
BRD4 PROTAC degrader MZ1 exerts anticancer effects in acute myeloid leukemia by targeting c-Myc and ANP32B genes.
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BRD4 PROTAC 降解剂 MZ1 通过靶向 c-Myc 和 ANP32B 基因在急性髓系白血病中发挥抗癌作用
DOI：
10.1080/15384047.2022.2125748
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发表时间：
2022-12-31
影响因子：
3.6
通讯作者：
Hu, Shaoyan
中科院分区：
文献类型：
--
作者：
Ma, Li;Wang, Jianwei;Zhang, Yongping;Fang, Fang;Ling, Jing;Chu, Xinran;Zhang, Zimu;Tao, Yanfang;Li, Xiaolu;Tian, Yuanyuan;Li, Zhiheng;Sang, Xu;Zhang, Kunlong;Lu, Lihui;Wan, Xiaomei;Chen, Yanling;Yu, Juanjuan;Zhuo, Ran;Wu, Shuiyan;Lu, Jun;Pan, Jian;Hu, Shaoyan
摘要急性髓细胞白血病（AML）是一种高度恶性、侵袭性的血液系统疾病，其耐药性和复发率高，死亡率高。最近，溴结构域和额外末端（BET）蛋白抑制剂作为潜在的抗癌剂在血液肿瘤中被广泛研究。MZ 1是一种新型BET抑制剂，通过蛋白水解靶向嵌合体（PROTAC）技术介导选择性蛋白降解和抑制肿瘤生长。因此，本研究的目的是探讨MZ 1在AML中的作用和治疗潜力。在这项研究中，我们首先确定了BRD 4高表达的AML患者的总生存率低于低表达组。MZ 1在体外抑制AML细胞生长并诱导细胞凋亡和周期阻滞。MZ 1诱导AML细胞株中BRD 4、BRD 3和BRD 2的降解。此外，MZ 1还启动聚ADP核糖聚合酶（PARP）的切割，其对代表AML不同分子亚型的NB 4（PML-RARa）、K562（BCR-ABL）、Kasumi-1（AML 1-ETO）和MV 4 -11（MLL-AF 4）细胞系显示出细胞毒性作用。在AML小鼠白血病模型中，MZ 1显著降低白血病细胞生长，并延长小鼠存活时间。根据RNA测序分析，MZ 1导致AML细胞系中c-Myc和ANP 32 B基因显著下调。ANP 32 B基因的敲除可促进AML细胞凋亡，抑制细胞生长。总之，我们的数据表明，MZ 1对具有不同分子病变的AML细胞系具有广泛的抗癌作用，这可能被开发为AML患者的新治疗策略。
ABSTRACT Acute myeloid leukemia (AML) is a highly cancerous and aggressive hematologic disease with elevated levels of drug resistance and relapse resulting in high mortality. Recently, bromodomains and extra-terminal (BET) protein inhibitors have been extensively researched in hematological tumors as potential anticancer agents. MZ1 is a novel BET inhibitor that mediates selective proteins degradation and suppression of tumor growth through proteolysis-targeting chimeras (PROTAC) technology. Accordingly, this study aimed to investigate the role and therapeutic potential of MZ1 in AML. In this study, we first identified that AML patients with high BRD4 expression had poor overall survival than those with low expression group. MZ1 inhibited AML cell growth and induced apoptosis and cycle arrest in vitro. MZ1 induced degradation of BRD4, BRD3 and BRD2 in AML cell strains. Additionally, MZ1 also initiated the cleavage of poly-ADP-ribose polymerase (PARP), which showed cytotoxic effects on NB4 (PML-RARa), K562 (BCR-ABL), Kasumi-1 (AML1-ETO), and MV4-11 (MLL-AF4) cell lines representing different molecular subtypes of AML. In AML mouse leukemia model, MZ1 significantly decreased leukemia cell growth and increased the mouse survival time. According to the RNA-sequencing analysis, MZ1 led to c-Myc and ANP32B genes significant downregulation in AML cell lines. Knockdown of ANP32B promoted AML cell apoptosis and inhibited cell growth. Overall, our data indicated that MZ1 had broad anti-cancer effects on AML cell lines with different molecular lesions, which might be exploited as a novel therapeutic strategy for AML patients.
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影响因子：
7.3
作者：
Chan KH;Zengerle M;Testa A;Ciulli A
通讯作者：
Ciulli A
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
3.7
作者：
Ohno Y;Koizumi M;Nakayama H;Watanabe T;Hirooka M;Tokumoto Y;Kuroda T;Abe M;Fukuda S;Higashiyama S;Kumagi T;Hiasa Y
通讯作者：
Hiasa Y
影响因子：
5.6
作者：
Hu Y;Zhou J;Ye F;Xiong H;Peng L;Zheng Z;Xu F;Cui M;Wei C;Wang X;Wang Z;Zhu H;Lee P;Zhou M;Jiang B;Zhang DY
通讯作者：
Zhang DY
影响因子：
6.4
作者：
Goundiam, Oumou;Gestraud, Pierre;Sastre-Garau, Xavier
通讯作者：
Sastre-Garau, Xavier