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

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.

Targeting AraC-Resistant Acute Myeloid Leukemia by Dual Inhibition of CDK9 and Bcl-2: A Systematic Review and Meta-Analysis

“…In most cancers, CDKs openly used as vital transcriptional regulators (e.g., CDK9) for consistent production of short-lived gene products that support cell survival [ 29 ]. Therefore, CDK9 pathway dysregulation is seen in various malignancies, making it a key anticancer target [ 30 ]. This approach has been used to initiate the discovery of CDK9 inhibitors by conducting human clinical trials [ 31 ].…”

Ginsenoside Rh2 Inhibits Glycolysis through the STAT3/c-MYC Axis in Non-Small-Cell Lung Cancer

“…\In addition to tumorigenesis, STAT3 and c-Myc play important roles in facilitating tumor cell glycolysis [ 11 , 12 ]. Therefore, we investigated the potential effect of Rh2 on the STAT3/c-Myc axis.…”

“…For example, Rg3 inhibited the Warburg effect in ovarian cancer cells and gliomas via targeting microRNA or long noncoding RNA [ 23 , 27 ]. Furthermore, it has been reported that STAT3 acts as a transcription factor to promote the expression of hexosaccharide kinase 2, which is a major glycolysis rate-limiting enzyme, resulting in glycolysis promotion [ 11 ] and c-Myc could also participate in glutamate metabolism to catalyze the decomposition of glutamine to produce lactate [ 12 ]. Thus, the STAT3/c-Myc axis plays crucial roles in glycolysis regulation.…”

One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies

“…suggested mechanism involving downregulation of MYC and the rate-limiting enzymes GLUT1, HK2, and LDHA [224,225]. In the presence of oxygen, normal cells metabolise their glucose to pyruvate, which is then completely oxidised to CO2 and H2O via the TCA cycle and oxidative phosphorylation.…”

“…In MLL-AF9-induced murine AML, glycolysis is supported by AMP-activated protein kinase (AMPK) [ 209 ], whereas, in T-ALL, glycolysis is supported by the oncogenic NOTCH [ 210 , 211 ]. Interestingly, in B-ALL- and BCR-ABL-driven CML, inhibition of cyclin-dependent kinases (CDKs) has been shown to restrain glycolytic metabolism by a suggested mechanism involving downregulation of MYC and the rate-limiting enzymes GLUT1, HK2, and LDHA [ 224 , 225 ].…”