CDK9 Inhibitor Induces the Apoptosis of B-Cell Acute Lymphocytic Leukemia by Inhibiting c-Myc-Mediated Glycolytic Metabolism

• Main Authors: Wen-Li Huang, Tuersunayi Abudureheman, Jing Xia, Lei Chu, Hang Zhou, Wei-Wei Zheng, Neng Zhou, Rong-Yi Shi, Ming-Hao Li, Jian-Min Zhu, Kai Qing, Chao Ji, Kai-Wei Liang, Sa Guo, Gang Yin, Cai-Wen Duan
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-03-01
• Series: Frontiers in Cell and Developmental Biology
• Subjects: CDK9 inhibitors; cell apoptosis; glycolysis; c-Myc; B-cell acute lymphocytic leukemia
• Online Access: https://www.frontiersin.org/articles/10.3389/fcell.2021.641271/full

B-cell acute lymphocytic leukemia (B-ALL), a common blood cancer in children, leads to high mortality. Cyclin-dependent kinase 9 inhibitor (CDK9i) effectively attenuates acute myeloid leukemia and chronic lymphoblastic leukemia by inducing apoptosis and inhibiting cell proliferation. However, the effect of CDK9i on B-ALL cells and the underlying mechanisms remain unclear. In this study, we showed that CDK9i induced the apoptosis of B-ALL cells in vitro by activating the apoptotic pathways. In addition, CDK9i restrained the glycolytic metabolism of B-ALL cells, and CDK9i-induced apoptosis was enhanced by co-treatment with glycolysis inhibitors. Furthermore, CDK9i restained the glycolysis of B-ALL cell lines by markedly downregulating the expression of glucose transporter type 1 (GLUT1) and the key rate-limiting enzymes of glycolysis, such as hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). Moreover, cell apoptosis was rescued in B-ALL cells with over-expressed c-Myc after treatment with CDK9i, which is involved in the enhancement of glycolytic metabolism. In summary, our findings suggest that CDK9 inhibitors induce the apoptosis of B-ALL cells by inhibiting c-Myc-mediated glycolytic metabolism, thus providing a new strategy for the treatment of B-ALL.