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Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis

Author

Listed:
  • Maryam Ghashghaei

    (University of British Columbia
    British Columbia Cancer Research Centre Vancouver)

  • Yilin Liu

    (British Columbia Cancer Research Centre Vancouver
    University of British Columbia)

  • James Ettles

    (CRUK Beatson Institute
    University of Glasgow)

  • Giuseppe Bombaci

    (Indiana University Simon Comprehensive Cancer Center)

  • Niveditha Ramkumar

    (British Columbia Cancer Research Centre Vancouver)

  • Zongmin Liu

    (University of British Columbia
    British Columbia Cancer Research Centre Vancouver)

  • Leo Escano

    (British Columbia Cancer Research Centre Vancouver)

  • Sandra Spencer Miko

    (British Columbia Cancer Research Centre)

  • Yerin Kim

    (British Columbia Cancer Research Centre Vancouver
    University of British Columbia)

  • Joseph A. Waldron

    (CRUK Beatson Institute
    University of Glasgow)

  • Kim Do

    (Memorial Sloan Kettering Cancer Center)

  • Kyle MacPherson

    (British Columbia Cancer Research Centre Vancouver)

  • Katie A. Yuen

    (British Columbia Cancer Research Centre Vancouver)

  • Thilelli Taibi

    (British Columbia Cancer Research Centre Vancouver)

  • Marty Yue

    (British Columbia Cancer Research Centre Vancouver)

  • Aaremish Arsalan

    (British Columbia Cancer Research Centre Vancouver)

  • Zhen Jin

    (University of British Columbia
    British Columbia Cancer Research Centre Vancouver)

  • Glenn Edin

    (British Columbia Cancer Research Centre Vancouver)

  • Aly Karsan

    (British Columbia Cancer Research Centre)

  • Gregg B. Morin

    (British Columbia Cancer Research Centre
    University of British Columbia)

  • Florian Kuchenbauer

    (British Columbia Cancer Research Centre Vancouver)

  • Fabiana Perna

    (Indiana University Simon Comprehensive Cancer Center
    Moffit Cancer Center)

  • Martin Bushell

    (CRUK Beatson Institute
    University of Glasgow)

  • Ly P. Vu

    (University of British Columbia
    British Columbia Cancer Research Centre Vancouver)

Abstract

Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML.

Suggested Citation

  • Maryam Ghashghaei & Yilin Liu & James Ettles & Giuseppe Bombaci & Niveditha Ramkumar & Zongmin Liu & Leo Escano & Sandra Spencer Miko & Yerin Kim & Joseph A. Waldron & Kim Do & Kyle MacPherson & Katie, 2024. "Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46665-2
    DOI: 10.1038/s41467-024-46665-2
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    References listed on IDEAS

    as
    1. Palaniraja Thandapani & Andreas Kloetgen & Matthew T. Witkowski & Christina Glytsou & Anna K. Lee & Eric Wang & Jingjing Wang & Sarah E. LeBoeuf & Kleopatra Avrampou & Thales Papagiannakopoulos & Aris, 2022. "Valine tRNA levels and availability regulate complex I assembly in leukaemia," Nature, Nature, vol. 601(7893), pages 428-433, January.
    2. Hao Du & Ya Zhao & Jinqiu He & Yao Zhang & Hairui Xi & Mofang Liu & Jinbiao Ma & Ligang Wu, 2016. "YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex," Nature Communications, Nature, vol. 7(1), pages 1-11, November.
    Full references (including those not matched with items on IDEAS)

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