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

Abstract

Cells from patients with acute myeloid leukemia (AML) that remain dormant and protected by stromal cells may escape effects of chemotherapy. We modeled 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 leukemia-associated phenotypes (LAPs) were cultured on stromal cells. The chemosensitivity of dormant (PKH26^high), CD34+, LAP+ cells was ascertained by 5-colour flow cytometric counting after 12 d. The PKH26^high, CD34+, LAP + subset retained clonogenic capacity. The dormant fraction was completely resistant to Ara-C (p = .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 leukemia cells, thought to contribute to disease relapse, and shown sensitivity of dormant LAP+ cells to ABT-199 and ABT-737 in this system.

Keywords:

• AML
• ABT-199
• ABT-737
• dormancy

Acknowledgements

NY was supported by the Nottinghamshire Leukaemia Appeal.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2018.1434884.