Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML

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Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML

Warfvinge, Rebecca (author): Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine

Geironson Ulfsson, Linda (author): Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine

Sommarin, Mikael N E (author): Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine

Lang, Stefan (author): Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine

Karlsson, Christine (author): Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine

Roschupkina, Teona (author): Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine

Stenke, Leif (author): Karolinska Institutet

Stentoft, Jesper (author): Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark.,Aarhus University Hospital

Olsson-Strömberg, Ulla (author): Uppsala universitet,Hematologi,Uppsala University Hospital

Hjorth-Hansen, Henrik (author): St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Trondheim, Norway.,St. Olav’s University Hospital

Mustjoki, Satu (author): Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland.;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland.,University of Helsinki

Soneji, Shamit (author): Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine

Richter, Johan (author): Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine

Karlsson, Göran (author): Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine

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AMER SOC HEMATOLOGY, 2017
2017
English.
In: Blood. - : AMER SOC HEMATOLOGY. - 0006-4971 .- 1528-0020. ; 129:17, s. 2384-2394

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Journal article (peer-reviewed)

Abstract Subject headings

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 immunopheno-typic 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(-/low) CD45RA(-) cKIT(-) CD26(+) population as a potential therapeutic target for improved therapy response.

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By the author/editor: Warfvinge, Rebec ...; Geironson Ulfsso ...; Sommarin, Mikael ...; Lang, Stefan; Karlsson, Christ ...; Roschupkina, Teo ...; show more...; Stenke, Leif; Stentoft, Jesper; Olsson-Strömberg ...; Hjorth-Hansen, H ...; Mustjoki, Satu; Soneji, Shamit; Richter, Johan; Karlsson, Göran; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Hematology

Articles in the publication: Blood

By the university: Uppsala University; Lund University; Karolinska Institutet

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Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML

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