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

• Published in: Leukemia 2020-06, Vol.34 (6), p.1613-1625
• Main Authors: Kinstrie, Ross, Horne, Gillian A., Morrison, Heather, Irvine, David, Munje, Chinmay, Castañeda, Eduardo Gómez, Moka, Hothri A., Dunn, Karen, Cassels, Jennifer E., Parry, Narissa, Clarke, Cassie J., Scott, Mary T., Clark, Richard E., Holyoake, Tessa L., Wheadon, Helen, Copland, Mhairi
• Format: Article
• Language: English
• Subjects: 13/100; 13/31; 38/32; 38/39; 38/61; 38/77; 631/67/71; 64/60; 692/699/1541/1990/283/1896; 96/106; 96/63; Analysis; Animals; BCR-ABL protein; Biomarkers, Tumor - analysis; Cancer Research; CD34 antigen; CD38 antigen; CD90 antigen; Cell survival; Chronic myeloid leukemia; Critical Care Medicine; Dasatinib; Dipeptidyl-peptidase IV; Drug Resistance, Neoplasm - physiology; Enzyme inhibitors; Fusion protein; Genes; Health aspects; Hematology; Heterografts; Humans; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Medical equipment and supplies industry; Medical test kit industry; Medicine; Medicine & Public Health; Membrane Glycoproteins - metabolism; Mice; Minimal residual disease; Myeloid leukemia; Neoplasm, Residual - metabolism; Neoplasm, Residual - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nilotinib; Oncology; Patients; Pharmaceutical industry; Phenols; Population; Progenitor cells; Protein Kinase Inhibitors - pharmacology; Receptors, Complement - metabolism; Stem cells; Survival; Transplantation; Tyrosine; Tyrosine kinase inhibitors; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-019-0684-5

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.