Efficacy of cyclin-dependent-kinase 9 inhibitors in a murine model of mixed-lineage leukemia

Garcia-Cuellar MP, Füller E, Mäthner E, Breitinger C, Hetzner K, Zeitlmann L, Borkhardt A, Slany R (2014)

Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2014

Journal

Leukemia Springer Nature

Publisher: Nature Publishing Group

Book Volume: 28

Pages Range: 1427-1435

Journal Issue: 7

DOI: 10.1038/leu.2014.40

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. © 2014 Macmillan Publishers Limited.

Authors with CRIS profile

Emanuel Mäthner Lehrstuhl für Genetik Constanze Breitinger Lehrstuhl für Genetik Katrin Hetzner Lehrstuhl für Genetik Robert Slany Lehrstuhl für Genetik

Involved external institutions

Heinrich-Heine-Universität Düsseldorf DE Germany (DE) Ingenium Pharmaceuticals AG DE Germany (DE)

How to cite

APA:

Garcia-Cuellar, M.-P., Füller, E., Mäthner, E., Breitinger, C., Hetzner, K., Zeitlmann, L.,... Slany, R. (2014). Efficacy of cyclin-dependent-kinase 9 inhibitors in a murine model of mixed-lineage leukemia. Leukemia, 28(7), 1427-1435. https://doi.org/10.1038/leu.2014.40

MLA:

Garcia-Cuellar, M-P, et al. "Efficacy of cyclin-dependent-kinase 9 inhibitors in a murine model of mixed-lineage leukemia." Leukemia 28.7 (2014): 1427-1435.

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