{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Truong P"],"funding":["Cancer Institute NSW (Cancer Institute New South Wales)","Department of Health | National Health and Medical Research Council (NHMRC)"],"pagination":["7360"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11358519"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["15(1)"],"pubmed_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"],"journal":["Nature communications"],"pubmed_title":["TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells."],"pmcid":["PMC11358519"],"funding_grant_id":["GNT2011627","TPG2152"],"pubmed_authors":["Afrasiabi A","Stonehouse O","Lock RB","Alinejad-Rokny H","Connerty P","Kakadia PM","Larsson J","Jolly CJ","Zou X","Mohamed S","Toscan CE","Islam MI","Ghodousi ES","Shen S","Joshi S","Nguyen M","Bhuyan GS","Thoms JAI","Bohlander SK","Walkley CR","Raftery MJ","Pimanda JE","Sarowar CH","Truong P","Zhong L","Michie KA"],"additional_accession":[]},"is_claimable":false,"name":"TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells.","description":"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","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Aug","modification":"2025-04-26T11:43:23.176Z","creation":"2025-04-06T13:45:30.947Z"},"accession":"S-EPMC11358519","cross_references":{"pubmed":["39198401"],"doi":["10.1038/s41467-024-51646-6"]}}