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

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. Sarowar, Elaheh S. Ghodousi, Olivia Stonehouse, Sara Mohamed, Cara E. Toscan, Patrick Connerty, Purvi M. Kakadia, Stefan K. Bohlander, Katharine A. Michie, Jonas Larsson, Richard B. Lock, Carl R. Walkley, Julie A. I. Thoms, Christopher J. Jolly () and John E. Pimanda ()
Additional contact information
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
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
Cara E. Toscan: UNSW Sydney
Patrick Connerty: 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
Carl R. Walkley: University of Melbourne
Julie A. I. Thoms: UNSW Sydney
Christopher J. Jolly: UNSW Sydney
John E. Pimanda: UNSW Sydney

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51646-6

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