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The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors

Author

Listed:
  • Lina Liu

    (McMaster University
    McMaster University
    University of Toronto
    University Health Network)

  • Ana Vujovic

    (University of Toronto
    University Health Network)

  • Nandan P. Deshpande

    (University of New South Wales
    University of New South Wales)

  • Shashank Sathe

    (University of California at San Diego)

  • Govardhan Anande

    (University of New South Wales
    University of New South Wales)

  • He Tian Tony Chen

    (McMaster University
    University Health Network)

  • Joshua Xu

    (McMaster University
    University Health Network)

  • Mark D. Minden

    (University of Toronto
    University Health Network)

  • Gene W. Yeo

    (University of California at San Diego)

  • Ashwin Unnikrishnan

    (University of New South Wales
    University of New South Wales)

  • Kristin J. Hope

    (University of Toronto
    University Health Network)

  • Yu Lu

    (McMaster University)

Abstract

Chemo-resistance in acute myeloid leukemia (AML) patients is driven by leukemic stem cells (LSCs) resulting in high rates of relapse and low overall survival. Here, we demonstrate that upregulation of the splicing factor, RBM17 preferentially marks and sustains LSCs and directly correlates with shorten patient survival. RBM17 knockdown in primary AML cells leads to myeloid differentiation and impaired colony formation and in vivo engraftment. Integrative multi-omics analyses show that RBM17 repression leads to inclusion of poison exons and production of nonsense-mediated decay (NMD)-sensitive transcripts for pro-leukemic factors and the translation initiation factor, EIF4A2. We show that EIF4A2 is enriched in LSCs and its inhibition impairs primary AML progenitor activity. Proteomic analysis of EIF4A2-depleted AML cells shows recapitulation of the RBM17 knockdown biological effects, including pronounced suppression of proteins involved in ribosome biogenesis. Overall, these results provide a rationale to target RBM17 and/or its downstream NMD-sensitive splicing substrates for AML treatment.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31155-0
    DOI: 10.1038/s41467-022-31155-0
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    References listed on IDEAS

    as
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