Resistance to FLT3 inhibition in an in vitro model of primary AML cells with a stem cell phenotype in a defined microenvironment

Abstract

Relapse in acute myeloid leukaemia (AML) is mediated by survival of leukaemic stem cells following remission-induction chemotherapy. It would therefore be useful to identify therapeutic agents that target leukaemic stem cells. We devised a flow cytometric chemosensitivity assay allowing 48 h culture of leukaemic blasts in a defined microenvironment followed by enumeration of viable CD34+CD38−CD123+ leukaemic stem and progenitor cells (LSPC). The assay was used to investigate the LSPC response to cytosine arabinoside (Ara-C) and to the FLT3 inhibitor AG1296. There was a 3.6-fold increase in Ara-C-treated LSPC survival under defined ‘niche-like’ conditions compared to culture without microenvironmental support. Nine AML samples with internal tandem duplications of FLT3 (FLT3/ITDs) were treated with AG1296. Three samples were very sensitive (>50% kill) and 4 were moderately sensitive (10–50% kill) in bulk suspension culture without microenvironmental support. However, under defined ‘niche-like’ conditions, the survival of LSPC was enhanced rather than inhibited by AG1296 treatment. We conclude that an interaction between LSPC and a defined in vitro microenvironment models a chemoresistant niche. Our data point to a need to investigate more novel chemotherapeutic agents under these stringent conditions to identify agents that may be suitable to target minimal residual disease in AML.

Citation

(2008). Resistance to FLT3 inhibition in an in vitro model of primary AML cells with a stem cell phenotype in a defined microenvironment. Leukemia, 22, 1395-1401. https://doi.org/10.1038/leu.2008.125

• Journal Article Type: Article
• Acceptance Date: Apr 24, 2008
• Online Publication Date: May 29, 2008
• Publication Date: 2008-07
• Deposit Date: Apr 5, 2024
• Journal: Leukemia
• Print ISSN: 0887-6924
• Electronic ISSN: 1476-5551
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 22
• Pages: 1395-1401
• DOI: https://doi.org/10.1038/leu.2008.125
• Public URL: https://nottingham-repository.worktribe.com/output/32755064
• Publisher URL: https://www.nature.com/articles/leu2008125