The BET inhibitor GNE-987 effectively induces anti-cancer effects in T-cell acute lymphoblastic leukemia by targeting enhancer regulated genes.

IF 3.3 3区 医学 Q2 ONCOLOGY
Juanjuan Yu, Yang Yang, Rongfang Zhou, Yanfang Tao, Frank Zhu, Wanyan Jiao, Zimu Zhang, Tongting Ji, Tiandan Li, Fang Fang, Yi Xie, Di Wu, Ran Zhuo, Xiaolu Li, Yanling Chen, Hongli Yin, Jianwei Wang, Jian Pan
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引用次数: 0

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy originating from T progenitor cells. It accounts for 15% of childhood and 25% of adult ALL cases. GNE-987 is a novel chimeric molecule developed using proteolysis-targeting chimeras (PROTAC) technology for targeted therapy. It consists of a potent inhibitor of the bromodomain and extraterminal (BET) protein, as well as the E3 ubiquitin ligase Von Hippel-Lindau (VHL), which enables the effective induction of proteasomal degradation of BRD4. Although GNE-987 has shown persistent inhibition of cell proliferation and apoptosis, its specific antitumor activity in T-ALL remains unclear. In this study, we aimed to investigate the molecular mechanisms underlying the antitumor effect of GNE-987 in T-ALL. To achieve this, we employed technologies including RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq) and CUT&Tag. The degradation of BET proteins, specifically BRD4, by GNE-987 has a profound impact on T-ALL cell. In in vivo experiments, sh-BRD4 lentivirus reduced T-ALL cell proliferation and invasion, extending the survival time of mice. The RNA-seq and CUT&Tag analyses provided further insights into the mechanism of action of GNE-987 in T-ALL. These analyses revealed that GNE-987 possesses the ability to suppress the expression of various genes associated with super-enhancers (SEs), including lymphoblastic leukemia 1 (LCK). By targeting these SE-associated genes, GNE-987 effectively inhibits the progression of T-ALL. Importantly, SE-related oncogenes like LCK were identified as critical targets of GNE-987. Based on these findings, GNE-987 holds promise as a potential novel candidate drug for the treatment of T-ALL.

BET 抑制剂 GNE-987 通过靶向增强子调控基因,有效诱导 T 细胞急性淋巴细胞白血病的抗癌作用。
T 细胞急性淋巴细胞白血病(T-ALL)是一种高度侵袭性的血液恶性肿瘤,起源于 T 祖细胞。它占儿童 ALL 病例的 15%,占成人 ALL 病例的 25%。GNE-987 是一种新型嵌合分子,采用蛋白水解靶向嵌合体 (PROTAC) 技术开发,用于靶向治疗。它是一种强效的溴化多聚酶域和外膜(BET)蛋白抑制剂,同时也是E3泛素连接酶Von Hippel-Lindau(VHL)的抑制剂,能有效诱导蛋白酶体降解BRD4。虽然GNE-987对细胞增殖和凋亡有持续抑制作用,但其在T-ALL中的特异性抗肿瘤活性仍不明确。本研究旨在探讨 GNE-987 在 T-ALL 中抗肿瘤作用的分子机制。为此,我们采用了RNA测序(RNA-seq)、染色质免疫沉淀测序(ChIP-seq)和CUT&Tag等技术。GNE-987对BET蛋白(尤其是BRD4)的降解对T-ALL细胞产生了深远的影响。在体内实验中,sh-BRD4慢病毒减少了T-ALL细胞的增殖和侵袭,延长了小鼠的存活时间。RNA-seq和CUT&Tag分析进一步揭示了GNE-987在T-ALL中的作用机制。这些分析表明,GNE-987能够抑制与超增强子(SE)相关的各种基因的表达,包括淋巴细胞白血病1(LCK)。通过靶向这些SE相关基因,GNE-987能有效抑制T-ALL的进展。重要的是,LCK 等 SE 相关致癌基因被确定为 GNE-987 的关键靶点。基于这些发现,GNE-987有望成为治疗T-ALL的新型候选药物。
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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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