IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-07620-0.html
   My bibliography  Save this article

SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4

Author

Listed:
  • Konstantinos Tzelepis

    (Wellcome Trust Sanger Institute
    Gurdon Institute and Department of Pathology)

  • Etienne Braekeleer

    (Wellcome Trust Sanger Institute)

  • Demetrios Aspris

    (Wellcome Trust Sanger Institute
    Karaiskakio Foundation)

  • Isaia Barbieri

    (University of Cambridge, Addenbrookes Hospital)

  • M. S. Vijayabaskar

    (Wellcome Trust Sanger Institute)

  • Wen-Hsin Liu

    (German Research Center for Environmental Health (HMGU))

  • Malgorzata Gozdecka

    (Wellcome Trust Sanger Institute
    University of Cambridge)

  • Emmanouil Metzakopian

    (University of Cambridge)

  • Hamish D. Toop

    (University of New South Wales
    Exonate Ltd, Milton Science Park)

  • Monika Dudek

    (Wellcome Trust Sanger Institute)

  • Samuel C. Robson

    (University of Portsmouth)

  • Francisco Hermida-Prado

    (Wellcome Trust Sanger Institute)

  • Yu Hsuen Yang

    (Wellcome Trust Sanger Institute)

  • Roya Babaei-Jadidi

    (University of New South Wales)

  • Dimitrios A. Garyfallos

    (Wellcome Trust Sanger Institute
    Genome Campus)

  • Hannes Ponstingl

    (Wellcome Trust Sanger Institute
    Genome Campus)

  • Joao M. L. Dias

    (University of Cambridge)

  • Paolo Gallipoli

    (University of Cambridge
    University of Cambridge
    Cambridge University Hospitals NHS Trust)

  • Michael Seiler

    (H3 Biomedicine Inc.)

  • Silvia Buonamici

    (H3 Biomedicine Inc.)

  • Binje Vick

    (German Research Center for Environmental Health (HMGU))

  • Andrew J. Bannister

    (Gurdon Institute and Department of Pathology)

  • Roland Rad

    (Department of Medicine II and TranslaTUM Cancer Center
    Heidelberg, & German Cancer Consortium (DKTK))

  • Rab K. Prinjha

    (GSK Medicines Research Centre)

  • John C. Marioni

    (University of Cambridge
    Wellcome Genome Campus
    Wellcome Trust Sanger Institute)

  • Brian Huntly

    (University of Cambridge
    University of Cambridge
    Cambridge University Hospitals NHS Trust)

  • Jennifer Batson

    (Exonate Ltd, Milton Science Park)

  • Jonathan C. Morris

    (University of New South Wales
    Exonate Ltd, Milton Science Park)

  • Cristina Pina

    (University of Cambridge)

  • Allan Bradley

    (Genome Campus)

  • Irmela Jeremias

    (German Research Center for Environmental Health (HMGU)
    Heidelberg, & German Cancer Consortium (DKTK)
    Ludwig Maximilians University München)

  • David O. Bates

    (Exonate Ltd, Milton Science Park
    Queen′s Medical Centre)

  • Kosuke Yusa

    (Wellcome Trust Sanger Institute)

  • Tony Kouzarides

    (Gurdon Institute and Department of Pathology)

  • George S. Vassiliou

    (Wellcome Trust Sanger Institute
    University of Cambridge
    University of Cambridge)

Abstract

We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4 and MED24. We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML.

Suggested Citation

  • Konstantinos Tzelepis & Etienne Braekeleer & Demetrios Aspris & Isaia Barbieri & M. S. Vijayabaskar & Wen-Hsin Liu & Malgorzata Gozdecka & Emmanouil Metzakopian & Hamish D. Toop & Monika Dudek & Samue, 2018. "SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07620-0
    DOI: 10.1038/s41467-018-07620-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-07620-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-018-07620-0?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:9:y:2018:i:1:d:10.1038_s41467-018-07620-0. 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.