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

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. https://doi.org/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 and Francis
• 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: https://nottingham-repository.worktribe.com/output/911381
• Publisher URL: https://www.tandfonline.com/doi/full/10.1080/10428194.2018.1434884
• 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.
• Contract Date: Mar 28, 2018