Abstract
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.
Highlights
B-cell acute lymphocytic leukemia (B-ALL) is a lymphocytic malignancy that frequently occurs in children and adults, which can infiltrate the bone marrow and extramedullary sites
Cell proliferation was assessed by staining with EdU, and the results showed that THZ1 treatment dramatically arrested B-ALL cells at the G2/M phase of cell cycle in a concentration and time-dependent manner (Figures 1D,E)
The RNA sequencing (RNA-SEQ) results displayed that THZ1 treatment significantly downregulated the expression of cell proliferation-related genes, such as CDK1, CDK2, CDK6, and CDK8, and upregulated the expression of cell cycle arrest-related genes, such as CDKN1A and CDKN1B (Figure 1F)
Summary
B-cell acute lymphocytic leukemia (B-ALL) is a lymphocytic malignancy that frequently occurs in children and adults, which can infiltrate the bone marrow and extramedullary sites. With recent advances in multi-modal chemotherapy regimens, the 5-year overall survival has reached 90% in children with B-ALL, whereas the outcome of older patients (≥40 years) remains poor [1]. THZ1 Induces Apoptosis of B-ALL drugs, and a proportion of patients cannot tolerate the sideeffects of multi-drug combination therapy [2]. Cyclin-dependent protein 7 (CDK7) is a member of the CDK family, which forms the trimeric complex CDK-activating kinase by combining with cyclin H and MAT1 and renders CDK7 uniquely involved in the regulation of transcription and cell cycle transitions. CDK7 is a potential drug target for the treatment of tumors. THZ1 is the first selective and covalent CDK7 inhibitor, which shows antitumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis [11,12,13,14]. Whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
