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

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, Y. 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.

doi:10.1101/2023.09.25.559286

bioRxiv · 10.1101/2023.09.25.559286

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

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, Y. 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.

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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 p27Kip1 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 p27Kip1, 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.

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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, Y. 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.. 2023-09-25. CDK8/19 Inhibition Attenuates G1 Arrest Induced by BCR-ABL Antagonists and Accelerates Death of Chronic Myelogenous Leukemia Cells. https://doi.org/10.1101/2023.09.25.559286

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