Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia
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Yuh-Ying Yeh1, Rong Chen2, Joshua Hessler1, Emilia Mahoney1, Amy M. Lehman3, Nyla A. Heerema4, Michael R. Grever1, William Plunkett2, John C. Byrd1,5 and Amy J. Johnson1,5
1 Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
2 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3 Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA
4 Department of Pathology, The Ohio State University, Columbus, Ohio, USA
5 Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
Amy J Johnson, email:
Keywords: Flavopiridol, Mcl-1, cyclin-dependent kinase 9 (CDK9), cyclin-dependent kinase (CDK) inhibitor, and leukemia
Received: May 9, 2014 Accepted: June 11, 2014 Published: June 12, 2014
Flavopiridol is a small molecule inhibitor of cyclin-dependent kinases (CDK) known to impair global transcription via inactivation of positive transcription elongation factor b. It has been demonstrated to have significant activity predominantly in chronic lymphocytic leukemia and acute myeloid leukemia in phase I/II clinical trials while other similar CDK inhibitors are vigorously being pursued in pre-clinical and clinical studies. Although flavopiridol is a potent therapeutic agent against blood diseases, some patients still have primary or acquired resistance throughout their clinical course. Considering the limited knowledge of resistance mechanisms of flavopiridol, we investigated the potential mechanisms of resistance to flavopiridol in a cell line system, which gradually acquired resistance to flavopiridol in vitro, and then confirmed the mechanism in patient samples. Herein, we present that this resistant cell line developed resistance through up-regulation of phosphorylation of RNA polymerase II C-terminal domain, activation of CDK9 kinase activity, and prolonged Mcl-1 stability to counter flavopiridol’s drug actions. Further analyses suggest MAPK/ERK activation-mediated Mcl-1 stabilization contributes to the resistance and knockdown of Mcl-1 in part restores sensitivity to flavopiridol-induced cytotoxicity. Altogether, these findings demonstrate that CDK9 is the most relevant target of flavopiridol and provide avenues to improve the therapeutic strategies in blood malignancies.
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