Abstract
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.
Highlights
B-cell acute lymphoblastic leukemia (B-ALL) is one of the most frequently occurring malignancies in children, with a peak incidence between 1 and 4 years of age
We discovered that CDK9 inhibitors induced the apoptosis of B-cell acute lymphocytic leukemia (B-ALL) cells by restraining glycolysis, which was enhanced by co-treatment with glycolysis inhibitors in vitro
We measured the cell proliferation by staining with EdU and found that EdU-positive B-ALL cells dramatically decreased after treatment with SNS-032 for 24 h (Figure 1B), and this result is consistent with a previous report in acute myeloid leukemia (AML) (Wang et al, 2019)
Summary
B-cell acute lymphoblastic leukemia (B-ALL) is one of the most frequently occurring malignancies in children, with a peak incidence between 1 and 4 years of age. CDK9 Inhibitors Induce Apoptosis of B-ALL no response to existing therapeutic drugs and suffered from the side-effects of long-term multi-drug treatment. The inhibition of the cell cycle is one of the key mechanisms in the development of drugs for leukemia treatment (Ghelli Luserna di Rora et al, 2017). Cyclin-dependent kinases (CDKs) are one family of serine/threonine protein kinases and regulate the cell cycle division and gene transcription. CDK9 modulates the transcription elongation and mRNA maturation of genes but does not regulate cell cycle of cells (Asghar et al, 2015). SNS-032, a CDK9 selective inhibitor, has entered clinical trials for the treatment of AML, CLL, and multiple myeloma (Tong et al, 2010; Walsby et al, 2011). The effect of CDK9 inhibitors on B-ALL cells and the underlying mechanism remain unknown
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