CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

Kinstrie, R. et al. (2020) CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy. Leukemia, 34(6), pp. 1613-1625. (doi: 10.1038/s41375-019-0684-5) (PMID:31896780) (PMCID:PMC7272220)

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Abstract

The introduction of BCR-ABL tyrosine kinase inhibitors has revolutionized the treatment of chronic myeloid leukemia (CML). A major clinical aim remains the identification and elimination of low-level disease persistence, termed “minimal residual disease”. The phenomenon of disease persistence suggests that despite targeted therapeutic approaches, BCR-ABL-independent mechanisms exist which sustain the survival of leukemic stem cells (LSCs). Although other markers of a primitive CML LSC population have been identified in the preclinical setting, only CD26 appears to offer clinical utility. Here we demonstrate consistent and selective expression of CD93 on a lin−CD34+CD38−CD90+ CML LSC population and show in vitro and in vivo data to suggest increased stem cell characteristics, as well as robust engraftment in patient-derived xenograft models in comparison with a CD93− CML stem/progenitor cell population, which fails to engraft. Through bulk and single-cell analyses of selected stem cell and cell survival-specific genes, we confirmed the quiescent character and demonstrate their persistence in a population of CML patient samples who demonstrate molecular relapse on TKI withdrawal. Taken together, our results identify that CD93 is consistently and selectively expressed on a lin−CD34+CD38−CD90+ CML LSC population with stem cell characteristics and may be an important indicator in determining poor TKI responders.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Parry, Narissa and Dunn, Mrs Karen and Moka, Miss Hothri Ananyamb and Scott, Dr Mary and Clarke, Dr Cassie and Morrison, Miss Heather and Horne, Dr Gillian and Gómez Castañeda, Eduardo and Kinstrie, Dr Ross and Munje, Dr Chinmay and Copland, Professor Mhairi and Holyoake, Professor Tessa and Irvine, Dr David and Wheadon, Professor Helen and Cassels, Miss Jennifer
Authors: Kinstrie, R., Horne, G., Morrison, H., Irvine, D., Munje, C., Gómez Castañeda, E., Moka, H. A., Dunn, K., Cassels, J., Parry, N., Clarke, C., Scott, M., Clark, R. E., Holyoake, T. L., Wheadon, H., and Copland, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Leukemia
Publisher:Nature Research
ISSN:0887-6924
ISSN (Online):1476-5551
Published Online:02 January 2020
Copyright Holders:Copyright © The Author(s) 2020
First Published:First published in Leukemia 34(6): 1613-1625
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
164891An investigation of the control of cell division and quiescence in leukaemic versus normal haemopoietic stem and progenitor cellsMhairi CoplandBloodwise (BLOODWIS)11017CS - Paul O'Gorman Leukaemia Research Centre
171051Targeting p53, cMyc and PRC2 regulatory hubs: A systematic and stratified approach to deliver new therapeutics for CMLDavid VetrieBloodwise (BLOODWIS)14033CS - Paul O'Gorman Leukaemia Research Centre
168119The importance of the Notch pathway and its interaction in the maintenance and progression of chronic myeloid leukaemiaMhairi CoplandWellcome Trust (WELLCOTR)100626/Z/12/ZCS - Paul O'Gorman Leukaemia Research Centre
161207Self-renewal pathway manipulation as a potential\r\ntherapeutic strategy for the eradication of Chronic Myeloid Leukaemia (CML)\r\nStem CellsDavid IrvineChief Scientist Office (CSO)CAF/08/09CS - Paul O'Gorman Leukaemia Research Centre
163632Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501CS - Paul O'Gorman Leukaemia Research Centre