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TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells

Author

Listed:
  • Peter Truong

    (UNSW Sydney)

  • Sylvie Shen

    (UNSW Sydney)

  • Swapna Joshi

    (UNSW Sydney)

  • Md Imtiazul Islam

    (UNSW Sydney)

  • Ling Zhong

    (UNSW Sydney)

  • Mark J. Raftery

    (UNSW Sydney)

  • Ali Afrasiabi

    (UNSW Sydney)

  • Hamid Alinejad-Rokny

    (UNSW Sydney
    UNSW Sydney)

  • Mary Nguyen

    (UNSW Sydney)

  • Xiaoheng Zou

    (UNSW Sydney)

  • Golam Sarower Bhuyan

    (UNSW Sydney)

  • Chowdhury H. Sarowar

    (UNSW Sydney)

  • Elaheh S. Ghodousi

    (UNSW Sydney)

  • Olivia Stonehouse

    (UNSW Sydney)

  • Sara Mohamed

    (UNSW Sydney
    Lowy Cancer Research Centre, UNSW Sydney
    UNSW Sydney)

  • Cara E. Toscan

    (UNSW Sydney
    Lowy Cancer Research Centre, UNSW Sydney
    UNSW Sydney)

  • Patrick Connerty

    (UNSW Sydney
    Lowy Cancer Research Centre, UNSW Sydney
    UNSW Sydney)

  • Purvi M. Kakadia

    (University of Auckland)

  • Stefan K. Bohlander

    (University of Auckland)

  • Katharine A. Michie

    (UNSW Sydney)

  • Jonas Larsson

    (Lund University)

  • Richard B. Lock

    (UNSW Sydney
    Lowy Cancer Research Centre, UNSW Sydney
    UNSW Sydney)

  • Carl R. Walkley

    (University of Melbourne
    University of Melbourne)

  • Julie A. I. Thoms

    (UNSW Sydney)

  • Christopher J. Jolly

    (UNSW Sydney)

  • John E. Pimanda

    (UNSW Sydney
    UNSW Sydney
    Prince of Wales Hospital)

Abstract

Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.

Suggested Citation

  • Peter Truong & Sylvie Shen & Swapna Joshi & Md Imtiazul Islam & Ling Zhong & Mark J. Raftery & Ali Afrasiabi & Hamid Alinejad-Rokny & Mary Nguyen & Xiaoheng Zou & Golam Sarower Bhuyan & Chowdhury H. S, 2024. "TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51646-6
    DOI: 10.1038/s41467-024-51646-6
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    References listed on IDEAS

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    2. Jeannine Diesch & Marguerite-Marie Le Pannérer & René Winkler & Raquel Casquero & Matthias Muhar & Mark van der Garde & Michael Maher & Carolina Martínez Herráez & Joan J. Bech-Serra & Michaela Fellne, 2021. "Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Yuanbin Song & Anthony Rongvaux & Ashley Taylor & Tingting Jiang & Toma Tebaldi & Kunthavai Balasubramanian & Arun Bagale & Yunus Kasim Terzi & Rana Gbyli & Xiaman Wang & Xiaoying Fu & Yimeng Gao & Ju, 2019. "A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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