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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
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    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.

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