CDK2-Mediated Upregulation of TNFα as a Mechanism of Selective Cytotoxicity in Acute Leukemia

Abstract

Although inhibitors of the kinases CHK1, ATR, and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines in vitro, including TP53-null acute myeloid leukemia (AML) and BCR/ABL–positive acute lymphoid leukemia (ALL), and inhibits leukemic colony formation in clinical AML samples ex vivo. In further studies, downregulation or inhibition of CHK1 triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNFα production, and engagement of a TNFR1- and BID-dependent apoptotic pathway. AML lines that were intrinsically resistant to CHK1 inhibition exhibited high CHK1 expression and were sensitized by CHK1 downregulation. Signaling through this same CDK2–AP1–TNF cytotoxic pathway was also initiated by ATR or WEE1 inhibitors in vitro and during CHK1 inhibitor treatment of AML xenografts in vivo. Collectively, these observations not only identify new contributors to the antileukemic cell action of CHK1, ATR, and WEE1 inhibitors, but also delineate a previously undescribed pathway leading from aberrant CDK2 activation to death ligand–induced killing that can potentially be exploited for acute leukemia treatment. Significance: This study demonstrates that replication checkpoint inhibitors can kill AML cells through a pathway involving AP1-mediated TNF gene activation and subsequent TP53-independent, TNFα-induced apoptosis, which can potentially be exploited clinically.

KIF11 serves as a cell cycle mediator in childhood acute lymphoblastic leukemia

“…Wang et al (31) reported the role of CDT1 in triggering PCa cell metastasis by driving cell cycle and EMT via the PI3K/AKT/GSK3β axis. Upregulated CDT1 in childhood ALL promotes cell proliferation, invasion and migration through activating EMT (32). CDK2 is widely involved in cell cycle progression, which, alongside its regulatory subunits are dysregulated, showing tumor-promoting features (33).…”

Mechanism of Bile‐Processed Coptidis Rhizoma to Treat Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Mellitus Based on UPLC‐Q‐TOF/MS and Network Pharmacology

“…CDK2 protein is a key protein in the control of the cell cycle and its over‐activation is a trigger for the development of many cancers. It has been shown that phosphorylation of CDK2 can activate downstream JNK proteins and promote the production of inflammatory factors [24] . In addition, CDK2 can cause steatosis in the liver via the CCAAT‐enhancer‐binding proteins/diacylglycerol acyltransferase 2 pathway [25] .…”

KIF11 serves as a cell cycle mediator in childhood acute lymphoblastic leukemia

“…Wang et al ( 2022 ) reported the role of CDT1 in triggering PCa cell metastasis by driving cell cycle and EMT via the PI3K/AKT/GSK3β axis. Upregulated CDT1 in childhood ALL promotes cell proliferation, invasion, and migration through activating EMT (Ding et al 2021 ). CDK2 is widely involved in cell cycle progression, which, alongside its regulatory subunits are dysregulated, showing tumor-promoting features (Shi et al 2021 ).…”