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

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.

HSV-1 and influenza infection induce linear and circular splicing of the long NEAT1 isoform

“…CH22) [79] with up to 24 h THZ1 treatment and a study on THZ1 treatment of B-cell acute lymphocytic leukemia cells (Nalm6) [80]. Realignment of corresponding samples confirmed linear splicing upon THZ1 treatment in all cell lines apart from DU145 and showed that splicing rates increased with the duration and dosage of THZ1 treatment (Fig 6A and 6B and S22A Fig).…”

“…Experiments identified with the Snaptron search cover prostate cancer (VCaP, LNCaP and DU145 cells) [ 42 ], bladder cancer (HCV-29 cells) [ 74 ], esophageal squamous cell carcinoma (TE7 and KYSE510 cells) [ 75 ], nasopharyngeal carcinoma (C666-1, HK1 and HNE1 cells) [ 76 ], pancreatic ductal adenocarcinoma (BxPC3, MiaPaCa-2 and PANC1 cells) [ 77 ] and chordoma (UM-Chor1 cells) [ 78 ]. Further literature search identified a second study of chordoma cells (UM-Chor1 and CH22) [ 79 ] with up to 24 h THZ1 treatment and a study on THZ1 treatment of B-cell acute lymphocytic leukemia cells (Nalm6) [ 80 ]. Realignment of corresponding samples confirmed linear splicing upon THZ1 treatment in all cell lines apart from DU145 and showed that splicing rates increased with the duration and dosage of THZ1 treatment ( Fig 6A and 6B and S22A Fig ).…”

Antileukemic activity of YPN-005, a CDK7 inhibitor, inducing apoptosis through c-MYC and FLT3 suppression in acute myeloid leukemia

“…These apoptosis-inducing antiproliferative effects of YPN-005 were related to inhibition of c-MYC and MCL1 expression consistent with previous reports. Several CDK7 inhibitors have showed anticancer effects by inducing cell apoptosis in AML, B-cell acute lymphoblastic leukemia, and solid tumors ( Abudureheman et al., 2021 ; Clark et al., 2017 ; Hu et al., 2019 ; T. Huang et al., 2019 ; Li et al., 2017 ; Zhang et al., 2019 ; Zhong et al., 2019 ). In addition, inhibition of CDK7 has been associated with decreased expression of c-MYC and MCL1 ( Clark et al., 2017 ; Li et al., 2017 ).…”

Gene Transcription as a Therapeutic Target in Leukemia

“…Although CDK7 has functions in transcription and cell cycle, the antitumor effect of CDK7 has been attributed to SE-associated transcriptional modulation [ 136 ]. THZ1 was efficient against T-ALL and peripheral T-cell lymphoma models (reviewed in [ 136 , 137 ]).…”