Original Article

Leukemia (2014) 28, 1427–1435; doi:10.1038/leu.2014.40; published online 11 February 2014

Molecular Targets for Therapy

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

M-P Garcia-Cuellar1, E Füller1, E Mäthner1, C Breitinger1, K Hetzner1, L Zeitlmann2, A Borkhardt3 and R K Slany1

  1. 1Department of Genetics, University Erlangen, Erlangen, Germany
  2. 2Ingenium Pharmaceuticals AG, Munich, Germany
  3. 3Clinic of Paediatric Oncology, Haematology and Clinical Immunology, Centre for Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

Correspondence: Professor RK Slany, Deptartment of Genetics, University Erlangen, Erwin Rommel Str. 3, Erlangen 91058, Germany. E-mail: rslany@biologie.uni-erlangen.de

Received 11 November 2013; Revised 10 January 2014; Accepted 15 January 2014
Accepted article preview online 21 January 2014; Advance online publication 11 February 2014

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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.

Keywords:

mixed-lineage leukemia; CDK9; inhibitor; preclinical study