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

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Kinstrie, Ross, Horne, Gillian A, Morrison, Heather, Irvine, David, Munje, Chinmay, Castaneda, Eduardo Gomez, Moka, Hothri A, Dunn, Karen, Cassels, Jennifer E, Parry, Narissa et al (show 6 more authors) , Clarke, Cassie J, Scott, Mary T, Clark, Richard E ORCID: 0000-0002-1261-3299, Holyoake, Tessa L, Wheadon, Helen and Copland, Mhairi (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.

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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:	Article
Uncontrolled Keywords:	Animals, Humans, Mice, Neoplasm, Residual, Membrane Glycoproteins, Receptors, Complement, Protein Kinase Inhibitors, Drug Resistance, Neoplasm, Neoplastic Stem Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Heterografts, Biomarkers, Tumor
Depositing User:	Symplectic Admin
Date Deposited:	19 Feb 2020 13:49
Last Modified:	19 Jan 2023 00:02
DOI:	10.1038/s41375-019-0684-5
Open Access URL:	https://www.nature.com/articles/s41375-019-0684-5
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3075730