CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism

• Main Authors: Tuersunayi Abudureheman, Jing Xia, Ming-Hao Li, Hang Zhou, Wei-Wei Zheng, Neng Zhou, Rong-Yi Shi, Jian-Min Zhu, Li-Ting Yang, Li Chen, Liang Zheng, Kai Xue, Kai Qing, Cai-Wen Duan
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-04-01
• Series: Frontiers in Oncology
• Subjects: B-cell acute lymphocytic leukemia; CDK7 inhibitor; cell apoptosis; metabolism; c-MYC
• Online Access: https://www.frontiersin.org/articles/10.3389/fonc.2021.663360/full

B-cell acute lymphocytic leukemia (B-ALL) is a malignant blood cancer that develops in children and adults and leads to high mortality. THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains obscure. In this study, we showed that THZ1 arrested the cell cycle of B-ALL cells in vitro in a low concentration, while inducing the apoptosis of B-ALL cells in vitro in a high concentration by activating the apoptotic pathways. In addition, RNA-SEQ results revealed that THZ1 disrupted the cellular metabolic pathways of B-ALL cells. Moreover, THZ1 suppressed the cellular metabolism and blocked the production of cellular metabolic intermediates in B-ALL cells. Mechanistically, THZ1 inhibited the cellular metabolism of B-ALL by downregulating the expression of c-MYC-mediated metabolic enzymes. However, THZ1 treatment enhanced cell apoptosis in over-expressed c-MYC B-ALL cells, which was involved in the upregulation of p53 expression. Collectively, our data demonstrated that CDK7 inhibitor THZ1 induced the apoptosis of B-ALL cells by perturbing c-MYC-mediated cellular metabolism, thereby providing a novel treatment option for B-ALL.