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The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

Author

Listed:
  • Ying Ge

    (University of Copenhagen
    University of Copenhagen
    University of Copenhagen)

  • Mikkel Bruhn Schuster

    (University of Copenhagen
    University of Copenhagen
    University of Copenhagen)

  • Sachin Pundhir

    (University of Copenhagen
    University of Copenhagen
    University of Copenhagen
    University of Copenhagen)

  • Nicolas Rapin

    (University of Copenhagen
    University of Copenhagen
    University of Copenhagen
    University of Copenhagen)

  • Frederik Otzen Bagger

    (University of Copenhagen
    University of Copenhagen
    University of Copenhagen
    University of Copenhagen)

  • Nikos Sidiropoulos

    (University of Copenhagen)

  • Nadia Hashem

    (University of Copenhagen
    University of Copenhagen
    University of Copenhagen)

  • Bo Torben Porse

    (University of Copenhagen
    University of Copenhagen
    University of Copenhagen)

Abstract

Cancer sequencing studies have implicated regulators of pre-mRNA splicing as important disease determinants in acute myeloid leukemia (AML), but the underlying mechanisms have remained elusive. We hypothesized that “non-mutated” splicing regulators may also play a role in AML biology and therefore conducted an in vivo shRNA screen in a mouse model of CEBPA mutant AML. This has led to the identification of the splicing regulator RBM25 as a novel tumor suppressor. In multiple human leukemic cell lines, knockdown of RBM25 promotes proliferation and decreases apoptosis. Mechanistically, we show that RBM25 controls the splicing of key genes, including those encoding the apoptotic regulator BCL-X and the MYC inhibitor BIN1. This mechanism is also operative in human AML patients where low RBM25 levels are associated with high MYC activity and poor outcome. Thus, we demonstrate that RBM25 acts as a regulator of MYC activity and sensitizes cells to increased MYC levels.

Suggested Citation

  • Ying Ge & Mikkel Bruhn Schuster & Sachin Pundhir & Nicolas Rapin & Frederik Otzen Bagger & Nikos Sidiropoulos & Nadia Hashem & Bo Torben Porse, 2019. "The splicing factor RBM25 controls MYC activity in acute myeloid leukemia," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08076-y
    DOI: 10.1038/s41467-018-08076-y
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    Cited by:

    1. Lina Liu & Ana Vujovic & Nandan P. Deshpande & Shashank Sathe & Govardhan Anande & He Tian Tony Chen & Joshua Xu & Mark D. Minden & Gene W. Yeo & Ashwin Unnikrishnan & Kristin J. Hope & Yu Lu, 2022. "The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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