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

Ning Yu; Claire Seedhouse; Nigel Russell; Monica Pallis

doi:10.1080/10428194.2018.1434884

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

Leuk Lymphoma. 2018 Oct;59(10):2447-2453. doi: 10.1080/10428194.2018.1434884. Epub 2018 Feb 12.

Authors

Ning Yu¹, Claire Seedhouse¹, Nigel Russell^{1

2}, Monica Pallis²

Affiliations

¹ a Department of Haematology , University of Nottingham , Nottingham , UK.
² b Centre for Clinical Haematology , Nottingham University Hospitals , Nottingham , UK.

PMID: 29431553
DOI: 10.1080/10428194.2018.1434884

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: ABT-199; ABT-737; AML; dormancy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Biphenyl Compounds / pharmacology*
Biphenyl Compounds / therapeutic use
Bone Marrow / pathology
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
Cell Line
Cell Proliferation / drug effects*
Coculture Techniques
Disease Progression
Drug Screening Assays, Antitumor
Humans
Leukemia, Myeloid, Acute / blood
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / pathology
Leukocytes, Mononuclear
Mice
Neoplasm Recurrence, Local / blood
Neoplasm Recurrence, Local / pathology
Neoplasm Recurrence, Local / prevention & control*
Nitrophenols / pharmacology*
Nitrophenols / therapeutic use
Piperazines / pharmacology
Piperazines / therapeutic use
Primary Cell Culture
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
Stromal Cells
Sulfonamides / pharmacology*
Sulfonamides / therapeutic use
Tumor Cells, Cultured

Substances

ABT-737
Antineoplastic Agents
BCL2 protein, human
Biphenyl Compounds
Bridged Bicyclo Compounds, Heterocyclic
Nitrophenols
Piperazines
Proto-Oncogene Proteins c-bcl-2
Sulfonamides
venetoclax