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Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML.
Warfvinge, Rebecca; Geironson, Linda; Sommarin, Mikael N E; Lang, Stefan; Karlsson, Christine; Roschupkina, Teona; Stenke, Leif; Stentoft, Jesper; Olsson-Strömberg, Ulla; Hjorth-Hansen, Henrik; Mustjoki, Satu; Soneji, Shamit; Richter, Johan; Karlsson, Göran.
Afiliación
  • Warfvinge R; Division of Molecular Hematology, and.
  • Geironson L; Division of Molecular Hematology, and.
  • Sommarin MNE; Division of Molecular Hematology, and.
  • Lang S; Division of Molecular Hematology, and.
  • Karlsson C; Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
  • Roschupkina T; Division of Molecular Hematology, and.
  • Stenke L; Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
  • Stentoft J; Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Olsson-Strömberg U; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
  • Hjorth-Hansen H; Department of Medical Science, and.
  • Mustjoki S; Division of Hematology, University Hospital, Uppsala, Sweden.
  • Soneji S; Department of Hematology, St. Olavs Hospital, Trondheim, Norway.
  • Richter J; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
  • Karlsson G; Hematology Research Unit Helsinki and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.
Blood ; 129(17): 2384-2394, 2017 04 27.
Article en En | MEDLINE | ID: mdl-28122740
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.
Asunto(s)
Antineoplásicos/uso terapéutico; Biomarcadores de Tumor/genética; Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico; Células Madre Neoplásicas/efectos de los fármacos; Inhibidores de Proteínas Quinasas/uso terapéutico; Análisis de la Célula Individual/métodos; ADP-Ribosil Ciclasa 1/deficiencia; ADP-Ribosil Ciclasa 1/genética; ADP-Ribosil Ciclasa 1/inmunología; Antígenos CD34/genética; Antígenos CD34/inmunología; Biomarcadores de Tumor/inmunología; Estudios de Casos y Controles; Linaje de la Célula/inmunología; Dipeptidil Peptidasa 4/genética; Dipeptidil Peptidasa 4/inmunología; Expresión Génica; Heterogeneidad Genética; Humanos; Inmunofenotipificación; Proteína Accesoria del Receptor de Interleucina-1/genética; Proteína Accesoria del Receptor de Interleucina-1/inmunología; Subunidad alfa del Receptor de Interleucina-2/genética; Subunidad alfa del Receptor de Interleucina-2/inmunología; Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico; Leucemia Mielógena Crónica BCR-ABL Positiva/genética; Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología; Antígenos Comunes de Leucocito/deficiencia; Antígenos Comunes de Leucocito/genética; Antígenos Comunes de Leucocito/inmunología; Células Madre Neoplásicas/inmunología; Células Madre Neoplásicas/patología; Proteínas Proto-Oncogénicas c-kit/deficiencia; Proteínas Proto-Oncogénicas c-kit/genética; Proteínas Proto-Oncogénicas c-kit/inmunología; Resultado del Tratamiento
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Leucemia Mielógena Crónica BCR-ABL Positiva / Biomarcadores de Tumor / Inhibidores de Proteínas Quinasas / Análisis de la Célula Individual / Antineoplásicos Tipo de estudio: Diagnostic_studies / Observational_studies Límite: Humans Idioma: En Revista: Blood Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Leucemia Mielógena Crónica BCR-ABL Positiva / Biomarcadores de Tumor / Inhibidores de Proteínas Quinasas / Análisis de la Célula Individual / Antineoplásicos Tipo de estudio: Diagnostic_studies / Observational_studies Límite: Humans Idioma: En Revista: Blood Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos