2. Academic Validation
  3. A kinase-independent role for CDK8 in BCR-ABL1+ leukemia

A kinase-independent role for CDK8 in BCR-ABL1+ leukemia

  • Nat Commun. 2019 Oct 18;10(1):4741. doi: 10.1038/s41467-019-12656-x.
Ingeborg Menzl 1,  Tinghu Zhang 2,  Angelika Berger-Becvar 1,  Reinhard Grausenburger 1,  Gerwin Heller 1 3 4,  Michaela Prchal-Murphy 1,  Leo Edlinger 1,  Vanessa M Knab 1,  Iris Z Uras 1,  Eva Grundschober 1,  Karin Bauer 5,  Mareike Roth 6,  Anna Skucha 7 8,  Yao Liu 2,  John M Hatcher 2,  Yanke Liang 2,  Nicholas P Kwiatkowski 2,  Daniela Fux 1,  Andrea Hoelbl-Kovacic 1,  Stefan Kubicek 8,  Junia V Melo 9 10,  Peter Valent 5,  Thomas Weichhart 11,  Florian Grebien 7 12,  Johannes Zuber 6,  Nathanael S Gray 2,  Veronika Sexl 13
Affiliations

Affiliations

  • 1 Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
  • 2 Department of Cancer Biology, Department of Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • 3 Department of Medicine I, Medical University of Vienna, Vienna, Austria.
  • 4 Comprehensive Cancer Center, Vienna, Austria.
  • 5 Division of Hematology and Hemostaseology, Department of Internal Medicine I, Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
  • 6 Research Institute of Molecular Pathology, Campus-Vienna-Biocenter 1, Vienna, Austria.
  • 7 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
  • 8 Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 9 Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, 5005, Australia.
  • 10 Department of Hematology, Imperial College London, Kensington, London, SW7 2AZ, UK.
  • 11 Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
  • 12 Institute for Medical Biochemistry, University of Veterinary Medicine, Vienna, Austria.
  • 13 Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria. veronika.sexl@vetmeduni.ac.at.
PMID: 31628323 DOI: 10.1038/s41467-019-12656-x
Abstract

Cyclin-dependent kinases (CDKs) are frequently deregulated in Cancer and represent promising drug targets. We provide evidence that CDK8 has a key role in B-ALL. Loss of CDK8 in leukemia mouse models significantly enhances disease latency and prevents disease maintenance. Loss of CDK8 is associated with pronounced transcriptional changes, whereas inhibiting CDK8 kinase activity has minimal effects. Gene set enrichment analysis suggests that the mTOR signaling pathway is deregulated in CDK8-deficient cells and, accordingly, these cells are highly sensitive to mTOR inhibitors. Analysis of large cohorts of human ALL and AML patients reveals a significant correlation between the level of CDK8 and of mTOR pathway members. We have synthesized a small molecule YKL-06-101 that combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells. We propose that simultaneous CDK8 degradation and mTOR inhibition might represent a potential therapeutic strategy for the treatment of ALL patients.

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