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Quantitative assessment of the sensitivity of dormant AML cells to the BAD mimetics ABT-199 and ABT-737

Yu, Ning; Seedhouse, Claire; Russell, Nigel; Pallis, Monica

Authors

Ning Yu

Nigel Russell

Monica Pallis



Abstract

Cells from patients with acute myeloid leukaemia (AML) that remain dormant and protected by stromal cells may escape effects of chemotherapy. We modelled dormancy in vitro and investigated the ability of Bcl-2 inhibitors ABT-199 and ABT-737 to overcome chemoprotection of dormant cells. CD34-enriched primary AML cells with aberrant leukaemia-associated phenotypes (LAPs) were cultured on stromal cells. The chemosensitivity of dormant (PKH26high), CD34+, LAP+ cells was ascertained by 5-colour flow cytometric counting after 12 days. The PKH26high, CD34+, LAP+ subset retained clonogenic capacity. The dormant fraction was completely resistant to ara-C (P=0.007). However, ABT-199 and ABT-737 were able to reduce the dormant fraction by 84% and 80% respectively of their effects on proliferating counterparts. In conclusion, we have elaborated a system for quantifying chemosensitivity in LAP+ dormant leukaemia cells thought to contribute to disease relapse, and shown sensitivity of dormant LAP+ cells to ABT-199 and ABT-737 in this system.

Citation

Yu, N., Seedhouse, C., Russell, N., & Pallis, M. (2018). Quantitative assessment of the sensitivity of dormant AML cells to the BAD mimetics ABT-199 and ABT-737. Leukemia & Lymphoma, 59(10), 2447-2453. doi:10.1080/10428194.2018.1434884

Journal Article Type Article
Acceptance Date Jan 23, 2018
Online Publication Date Feb 12, 2018
Publication Date 2018
Deposit Date Mar 28, 2018
Publicly Available Date Feb 13, 2019
Journal Leukemia and Lymphoma
Print ISSN 1042-8194
Electronic ISSN 1029-2403
Publisher Taylor & Francis Open
Peer Reviewed Peer Reviewed
Volume 59
Issue 10
Pages 2447-2453
DOI https://doi.org/10.1080/10428194.2018.1434884
Keywords AML; ABT-199; ABT-737; dormancy
Public URL http://eprints.nottingham.ac.uk/id/eprint/50748
Publisher URL https://www.tandfonline.com/doi/full/10.1080/10428194.2018.1434884
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf
Additional Information This is an Accepted Manuscript of an article published by Taylor & Francis in Leukemia and Lymphoma on 12 Feb 2018, available online: http://www.tandfonline.com/10.1080/10428194.2018.1434884.

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ABT-199 in dormant revised manuscript and figures.pdf (379 Kb)
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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