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Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia

Item Type:Article
Title:Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia
Creators Name:Ling, V.Y. and Straube, J. and Godfrey, W. and Haldar, R. and Janardhanan, Y. and Cooper, L. and Bruedigam, C. and Cooper, E. and Tavakoli Shirazi, P. and Jacquelin, S. and Tey, S.K. and Baell, J. and Huang, F. and Jin, J. and Zhao, Y. and Bullinger, L. and Bywater, M.J. and Lane, S.W.
Abstract:Chemotherapy-resistant acute myeloid leukemia (AML), frequently driven by clonal evolution, has a dismal prognosis. A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockouts involving AraC metabolism and genes that regulate cell cycle arrest (cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53) as contributing to resistance. In human AML cohorts, reduced expression of CDKN2A conferred inferior overall survival and CDKN2A downregulation occurred at relapse in paired diagnosis-relapse samples, validating its clinical relevance. Therapeutically targeting the G1S cell cycle restriction point (with CDK4/6 inhibitor, palbociclib and KAT6A inhibitor, WM-1119, to upregulate CDKN2A) synergized with chemotherapy. Additionally, direct promotion of apoptosis with venetoclax, showed substantial synergy with chemotherapy, overcoming resistance mediated by impaired cell cycle arrest. Altogether, we identify defective cell cycle arrest as a clinically relevant contributor to chemoresistance and identify rationally designed therapeutic combinations that enhance response in AML, potentially circumventing chemoresistance.
Keywords:Apoptosis, Cell Cycle, Cell Cycle Checkpoints, Tumor Cell Line, Cytarabine, Acute Myeloid Leukemia
Publisher:Nature Publishing Group
Page Range:143-153
Date:January 2023
Official Publication:https://doi.org/10.1038/s41375-022-01755-2
PubMed:View item in PubMed

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