CDK7 inhibition induces apoptosis in acute myeloid leukemia cells and exerts synergistic antileukemic effects with azacitidine in vitro and in vivo

Abstract

THZ1, a CDK7 inhibitor, has potent antitumor effects in several cancers; however, its role in Acute myeloid leukemia (AML) is unclear. We explored the effects and potential mechanisms of THZ1, alone and in combination with azacitidine (AZA), in AML cells and xenograft models. THZ1 decreased cell viability, induced apoptosis in a dose and time-dependent manner, induced G0/G1 cell cycle arrest, decreased phosphorylated CDK1 and CDK2 expression, and inhibited RNA Pol II phosphorylation at multiple serine sites. The combination of AZA and THZ1 exhibited synergistic antileukemic effects in AML cell lines and primary cells with MCL1 and c-MYC downregulation. Moreover, the combination therapy significantly decreased tumor burden and prolonged animal survival in xenograft mice models. Our data demonstrate that CDK7 inhibition induces the apoptosis of AML cells and exerts a synergistic antileukemia effect with AZA in vitro and in vivo, which supports future exploration of this combination in clinical studies.

Keywords:

• Acute myeloid leukemia
• CDK7 inhibitor
• azacitidine
• apoptosis
• c-MYC

Acknowledgments

We would like to thank AJE for their assistance in editing this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Original RNA sequencing data are available in The Genome Sequence Archive for Humans (https://ngdc.cncb.ac.cn/gsa-human/; Accession code: HRA002252). The datasets generated during the current study are available from the corresponding author upon reasonable request.

Additional information

Funding

This work was supported by grants from the National High Level Hospital Clinical Research Funding [No.BJ-2022-127], CAMS Innovation Fund for Medical Sciences [CIFMS, No. 2021-I2M-C&T-A-020], and the National Natural Science Foundation of China [No. 82104231].