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ACUTE MYELOID LEUKEMIA

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

Leukemia volume 37, pages 143–153 (2023)Cite this article

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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.

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Fig. 1: Brunello genome-wide CRISPR knockout screen investigating chemoresistance in AML cell lines.
Fig. 2: DCK inactivation diminishes cytotoxicity of combination chemotherapy in AML cells.
Fig. 3: CDKN2A and CHEK2 inactivation confer chemoresistance in OCI-AML3 cell lines.
Fig. 4: CDKN2A is a clinically relevant mediator of poor prognosis in human AML.
Fig. 5: Therapeutic targeting of G1S cell cycle restriction point with palbociclib potentiates apoptotic responses to chemotherapy.
Fig. 6: Promotion of apoptosis with venetoclax synergizes with chemotherapy in AML cell lines harboring defects in cell cycle arrest.

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Data availability

The RNA sequencing dataset generated and analyzed during the current study is available in the Gene Expression Omnibus repository (GSE205802).

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Acknowledgements

The work was funded through grants from the National Health and Medical Research Council (NHMRC), Australia (Postgraduate Scholarship to VYL, Fellowship to MJB and Fellowship to SWL), CSL Centenary Fellowship (SWL) and the Gordon and Jessie Gilmour Leukaemia Research Fund (SWL). The authors thank and acknowledge Marco Herold (Walter and Eliza Hall Institute, Melbourne, Australia) for provision of critical reagents and expert technical advice and Peter Adams and Xue Lei (Sanford Burnham Prebys, California, United States of America (USA)) for analysis of RNA sequencing data (shown in Supplementary Fig. 12) and helpful discussions. We further thank Geoffrey Hill (Fred Hutch Cancer Center, Washington, USA), Richard D’Andrea (University of South Australia, Adelaide, Australia), Jason Powell (University of South Australia) and Francine Garrett-Bakelman (University of Virginia, Virginia, USA) for helpful discussions. The authors thank all the members of the Translational Leukaemia Research laboratory, QIMR Berghofer Medical Research Institute (Brisbane, Australia) for helpful discussions and technical assistance and the QIMR Berghofer core facilities (including the animal facility, flow cytometry and sequencing laboratory) for technical assistance.

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  1. These authors contributed equally: Megan J. Bywater and Steven W. Lane.

Authors and Affiliations

  1. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

    Victoria Y. Ling, Jasmin Straube, William Godfrey, Rohit Haldar, Yashaswini Janardhanan, Leanne Cooper, Claudia Bruedigam, Emily Cooper, Paniz Tavakoli Shirazi, Siok-Keen Tey, Megan J. Bywater & Steven W. Lane

  2. Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia

    Victoria Y. Ling, Jasmin Straube, Claudia Bruedigam, Siok-Keen Tey, Megan J. Bywater & Steven W. Lane

  3. Princess Alexandra Hospital, Brisbane, QLD, Australia

    Victoria Y. Ling

  4. Mater Research, Brisbane, QLD, Australia

    Sebastien Jacquelin

  5. Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    Siok-Keen Tey & Steven W. Lane

  6. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

    Jonathan Baell, Jianwen Jin & Yichao Zhao

  7. School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, People’s Republic of China

    Jonathan Baell & Fei Huang

  8. Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

    Lars Bullinger

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Contributions

VYL, SJ, MJB and SWL conceived and designed the work. VYL, JS, WG, RH, YJ, LC, CB, EC, PTS, SJ and MJB acquired data and interpreted results. JB, FH, JJ and YZ designed and performed experiments to supply critical reagents. ST, JB and LB provided intellectual input and/or critical reagents and interpreted results. VYL, MJB and SWL wrote the manuscript. All authors revised the manuscript and approved the final version.

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Correspondence to Megan J. Bywater or Steven W. Lane.

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Ling, V.Y., Straube, J., Godfrey, W. et al. Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia. Leukemia 37, 143–153 (2023). https://doi.org/10.1038/s41375-022-01755-2

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