CDK8/19 Inhibition Attenuates G1 Arrest Induced by BCR-ABL Arrest Induced by Bcr-Abl Antagonists and Accelerates Death of Chronic Myelogenous Leukemia Cells

Author(s)

Alvina I. Khamidullina
Margarita A. Yastrebova
Alexandra V. Bruter
Julia V. Nuzhina
Nadezhda E. Vorobyeva
Anastasia M. Khrustaleva
Ekaterina A. Varlamova
Alexander V. Tyakht
Iaroslav E. Abramenko
Ekaterina S. Ivanova
Maria A. Zamkova
Jing Li
Chang-Uk Lim, University of South Carolina College of PharmacyFollow
Mengqian Chen, University of South Carolina College of PharmacyFollow
Eugenia V. Broude, University of South Carolina College of PharmacyFollow
Igor B. Roninson, University of South Carolina College of PharmacyFollow
Alexander A. Shtil
Victor V. Tatarskiy

Document Type

Article

Abstract

Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (BCR-ABLi) are the mainstay of chronic myelogenous leukemia (CML) treatment. However, activation of circumventing signaling pathways and quiescence may limit BCR-ABLi efficacy. CDK8/19 Mediator kinases have been implicated in the emergence of non-genetic drug resistance. Dissecting the effects of pharmacological CDK8/19 inhibition on CML survival in response to BCR-ABLi, we found that a selective, non-toxic CDK8/19 inhibitor (CDK8/19i) Senexin B (SenB) and other CDK8/19i sensitized K562 cells to different BCR-ABLi via attenuation of cell cycle arrest. In particular, SenB prevented IM-induced upregulation of genes that negatively regulate cell cycle progression. SenB also antagonized IM-activated p27^Kip1 elevation thereby diminishing the population of G1-arrested cells. After transient G1 arrest, cells treated with IM + SenB re-entered the S phase, where they were halted and underwent replicative stress. Consequently, the combination of IM and SenB intensified apoptotic cell death, measured by activation of caspase 9 and 3, subsequent cleavage of poly(ADPriboso)polymerase 1, positive Annexin V staining and increase of subG1 fraction. In contrast, IM-treated BCR-ABL-positive KU812 CML cells, which did not induce p27^Kip1, readily died regardless of SenB treatment. Thus, CDK8/19i prevent the quiescence-mediated escape from BCR-ABLi-induced apoptosis, suggesting a strategy for avoiding the CML relapse.

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41420-025-02339-6

Publication Info

Published in Cell Death Discovery, Volume 11, Issue 1, 2025.

Rights

© The Author(s) 2025 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

APA Citation

Khamidullina, A. I., Yastrebova, M. A., Bruter, A. V., Nuzhina, J. V., Vorobyeva, N. E., Khrustaleva, A. M., Varlamova, E. A., Tyakht, A. V., Abramenko, I. E., Ivanova, E. S., Zamkova, M. A., Li, J., Lim, C.-U., Chen, M., Broude, E. V., Roninson, I. B., Shtil, A. A., & Tatarskiy, V. V. (2025). CDK8/19 inhibition attenuates G1 arrest induced by BCR-ABL antagonists and accelerates death of chronic myelogenous leukemia cells. Cell Death Discovery, 11(1).https://doi.org/10.1038/s41420-025-02339-6