IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-15733-8.html
   My bibliography  Save this article

MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia

Author

Listed:
  • Svetlana S. Itskovich

    (Cincinnati Children’s Hospital Medical Center)

  • Arun Gurunathan

    (Cincinnati Children’s Hospital Medical Center)

  • Jason Clark

    (Cincinnati Children’s Hospital Medical Center)

  • Matthew Burwinkel

    (Cincinnati Children’s Hospital Medical Center)

  • Mark Wunderlich

    (Cincinnati Children’s Hospital Medical Center)

  • Mikaela R. Berger

    (University of Cincinnati School of Medicine)

  • Aishwarya Kulkarni

    (University of Cincinnati
    Cincinnati Children’s Hospital Medical Center)

  • Kashish Chetal

    (Cincinnati Children’s Hospital Medical Center)

  • Meenakshi Venkatasubramanian

    (University of Cincinnati
    Cincinnati Children’s Hospital Medical Center)

  • Nathan Salomonis

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati School of Medicine)

  • Ashish R. Kumar

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati School of Medicine)

  • Lynn H. Lee

    (University of Cincinnati School of Medicine
    Cincinnati Children’s Hospital Medical Center)

Abstract

Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed in MLL-rearranged leukemias. We found that MBNL1 loss significantly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo. Through transcriptomic profiling of our experimental systems, we show that in leukemic cells, MBNL1 regulates alternative splicing (predominantly intron exclusion) of several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A. We finally show that selective leukemic cell death is achievable with a small molecule inhibitor of MBNL1. These findings provide the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of a burgeoning paradigm in targeted therapy, namely the disruption of cancer-specific splicing programs through the targeting of selectively essential RNA binding proteins.

Suggested Citation

  • Svetlana S. Itskovich & Arun Gurunathan & Jason Clark & Matthew Burwinkel & Mark Wunderlich & Mikaela R. Berger & Aishwarya Kulkarni & Kashish Chetal & Meenakshi Venkatasubramanian & Nathan Salomonis , 2020. "MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15733-8
    DOI: 10.1038/s41467-020-15733-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-15733-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-15733-8?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
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Aidan M. Fenix & Yuichiro Miyaoka & Alessandro Bertero & Steven M. Blue & Matthew J. Spindler & Kenneth K. B. Tan & Juan A. Perez-Bermejo & Amanda H. Chan & Steven J. Mayerl & Trieu D. Nguyen & Caitli, 2021. "Gain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Mariela Cortés-López & Laura Schulz & Mihaela Enculescu & Claudia Paret & Bea Spiekermann & Mathieu Quesnel-Vallières & Manuel Torres-Diz & Sebastian Unic & Anke Busch & Anna Orekhova & Monika Kuban &, 2022. "High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

    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:11:y:2020:i:1:d:10.1038_s41467-020-15733-8. 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.