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

Ingeborg Menzl, Tinghu Zhang, Angelika Berger-Becvar, Reinhard Grausenburger, Gerwin Heller, Michaela Prchal-Murphy, Leo Edlinger, Vanessa M. Knab, Iris Z. Uras, Eva Grundschober, Karin Bauer, Mareike Roth, Anna Skucha, Yao Liu, John M. Hatcher, Yanke Liang, Nicholas P. Kwiatkowski, Daniela Fux, Andrea Hoelbl-Kovacic, Stefan Kubicek, Junia V. Melo, Peter Valent, Thomas Weichhart, Florian Grebien, Johannes Zuber, Nathanael S. Gray and Veronika Sexl ()
Additional contact information
Ingeborg Menzl: University of Veterinary Medicine
Tinghu Zhang: Dana-Farber Cancer Institute, Harvard Medical School
Angelika Berger-Becvar: University of Veterinary Medicine
Reinhard Grausenburger: University of Veterinary Medicine
Gerwin Heller: University of Veterinary Medicine
Michaela Prchal-Murphy: University of Veterinary Medicine
Leo Edlinger: University of Veterinary Medicine
Vanessa M. Knab: University of Veterinary Medicine
Iris Z. Uras: University of Veterinary Medicine
Eva Grundschober: University of Veterinary Medicine
Karin Bauer: Medical University of Vienna
Mareike Roth: Research Institute of Molecular Pathology
Anna Skucha: Ludwig Boltzmann Institute for Cancer Research
Yao Liu: Dana-Farber Cancer Institute, Harvard Medical School
John M. Hatcher: Dana-Farber Cancer Institute, Harvard Medical School
Yanke Liang: Dana-Farber Cancer Institute, Harvard Medical School
Nicholas P. Kwiatkowski: Dana-Farber Cancer Institute, Harvard Medical School
Daniela Fux: University of Veterinary Medicine
Andrea Hoelbl-Kovacic: University of Veterinary Medicine
Stefan Kubicek: Research Center for Molecular Medicine of the Austrian Academy of Sciences
Junia V. Melo: University of Adelaide
Peter Valent: Medical University of Vienna
Thomas Weichhart: Medical University of Vienna
Florian Grebien: Ludwig Boltzmann Institute for Cancer Research
Johannes Zuber: Research Institute of Molecular Pathology
Nathanael S. Gray: Dana-Farber Cancer Institute, Harvard Medical School
Veronika Sexl: University of Veterinary Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-12656-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12656-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-12656-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().