title: Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML.
abstract: Understanding leukemia heterogeneity is critical for the development of curative treatments as the failure to eliminate therapy-persistent leukemic stem cells (LSCs) may result in disease relapse. Here we have combined high-throughput immunophenotypic screens with large-scale single-cell gene expression analysis to define the heterogeneity within the LSC population in chronic phase chronic myeloid leukemia (CML) patients at diagnosis and following conventional tyrosine kinase inhibitor (TKI) treatment. Our results reveal substantial heterogeneity within the putative LSC population in CML at diagnosis and demonstrate differences in response to subsequent TKI treatment between distinct subpopulations. Importantly, LSC subpopulations with myeloid and proliferative molecular signatures are proportionally reduced at a higher extent in response to TKI therapy compared with subfractions displaying primitive and quiescent signatures. Additionally, cell surface expression of the CML stem cell markers CD25, CD26, and IL1RAP is high in all subpopulations at diagnosis but downregulated and unevenly distributed across subpopulations in response to TKI treatment. The most TKI-insensitive cells of the LSC compartment can be captured within the CD45RA-fraction and further defined as positive for CD26 in combination with an aberrant lack of cKIT expression. Together, our results expose a considerable heterogeneity of the CML stem cell population and propose a Lin-CD34+CD38-/lowCD45RA-cKIT-CD26+population as a potential therapeutic target for improved therapy response.
authors.affiliation: Division of Molecular Hematology, and.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Warfvinge
authors.affiliation: Division of Molecular Hematology, and.
authors.forename: Linda
authors.initials: L
authors.lastname: Geironson
authors.affiliation: Division of Molecular Hematology, and.
authors.forename: Mikael N E
authors.identifier: 0000-0002-2581-5543
authors.initials: MNE
authors.lastname: Sommarin
authors.affiliation: Division of Molecular Hematology, and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lang
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Christine
authors.initials: C
authors.lastname: Karlsson
authors.affiliation: Division of Molecular Hematology, and.
authors.forename: Teona
authors.initials: T
authors.lastname: Roschupkina
authors.affiliation: Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.|Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Stenke
authors.affiliation: Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Stentoft
authors.affiliation: Department of Medical Science, and.|Division of Hematology, University Hospital, Uppsala, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Olsson-Strömberg
authors.affiliation: Department of Hematology, St. Olavs Hospital, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hjorth-Hansen
authors.affiliation: Hematology Research Unit Helsinki and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.|Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; and.
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
authors.affiliation: Division of Molecular Hematology, and.
authors.forename: Shamit
authors.initials: S
authors.lastname: Soneji
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.|Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Richter
authors.affiliation: Division of Molecular Hematology, and.
authors.forename: Göran
authors.initials: G
authors.lastname: Karlsson
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D018952:Antigens, CD34 / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D019070:Cell Lineage / Q000276:immunology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D018740:Genetic Heterogeneity; D006801:Humans; D016130:Immunophenotyping; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D059010:Single-Cell Analysis / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C507765:IL1RAP protein, human; C508017:IL2RA protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D053645:Interleukin-2 Receptor alpha Subunit; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D017493:Leukocyte Common Antigens; D051997:ADP-ribosyl Cyclase 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4