Abstract
Mixed-lineage leukemia fusion proteins activate their target genes predominantly by stimulating transcriptional elongation. A core component necessary for this activity is cyclin-dependent kinase 9. Here we explored the effectiveness of small molecules targeting this enzyme as potential therapeutics. A screen of seven compounds with anti-CDK9 activity applied to a panel of leukemia cell lines identified flavopiridol and the experimental inhibitor PC585 as superior in efficacy with inhibitory concentrations in the submicromolar range. Both substances induced rapid dephosphorylation of the RNA polymerase II C-terminal domain, accompanied by downregulation of CDK9-dependent transcripts for MYC and HOXA9. Global gene expression analysis indicated the induction of a general stress response program, culminating in widespread apoptosis. Importantly, colony-forming activity in leukemia lines and primary patient samples could be completely inhibited under conditions that did not affect native precursors from bone marrow. In vivo application in a mouse transplant model significantly delayed disease with PC585 showing also oral activity. These results suggest CDK9 inhibition as novel treatment option for mixed-lineage leukemia.
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Acknowledgements
We thank Renate Zimmermann for technical assistance and Ingenium Pharmaceuticals for the generous provision with CDK9 inhibitors. This work was supported by research funding from Sander Stiftung, Grant 2010.069.1 to RKS.
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L Zeitlmann is an employee of Ingenium Pharmaceuticals. The other authors declare no conflict of interest.
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Garcia-Cuellar, MP., Füller, E., Mäthner, E. et al. Efficacy of cyclin-dependent-kinase 9 inhibitors in a murine model of mixed-lineage leukemia. Leukemia 28, 1427–1435 (2014). https://doi.org/10.1038/leu.2014.40
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DOI: https://doi.org/10.1038/leu.2014.40
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