IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-019-12656-x.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    Medical University of Vienna
    Comprehensive Cancer Center)

  • 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
    Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • 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
    Imperial College London, Kensington)

  • Peter Valent

    (Medical University of Vienna)

  • Thomas Weichhart

    (Medical University of Vienna)

  • Florian Grebien

    (Ludwig Boltzmann Institute for Cancer Research
    University of Veterinary Medicine)

  • Johannes Zuber

    (Research Institute of Molecular Pathology)

  • Nathanael S. Gray

    (Dana-Farber Cancer Institute, Harvard Medical School)

  • Veronika Sexl

    (University of Veterinary Medicine)

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.

Suggested Citation

  • 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 Baue, 2019. "A kinase-independent role for CDK8 in BCR-ABL1+ leukemia," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12656-x
    DOI: 10.1038/s41467-019-12656-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-019-12656-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-019-12656-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12656-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.