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

Autor: 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, John E. Pimanda
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Nature Communications, Vol 15, Iss 1, Pp 1-19 (2024)
Druh dokumentu: article
ISSN: 2041-1723
73815292
DOI: 10.1038/s41467-024-51646-6
Popis: 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.
Databáze: Directory of Open Access Journals
Externí odkaz: