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Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML
Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
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2017 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 129, no 17, 2384-2394 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY , 2017. Vol. 129, no 17, 2384-2394 p.
National Category
Hematology
Identifiers
URN: urn:nbn:se:uu:diva-322720DOI: 10.1182/blood-2016-07-728873ISI: 000400243100012PubMedID: 28122740OAI: oai:DiVA.org:uu-322720DiVA: diva2:1099176
Funder
Swedish Cancer SocietyRagnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationSwedish Research CouncilThe Crafoord FoundationRegion Skåne
Available from: 2017-05-29 Created: 2017-05-29 Last updated: 2017-05-29Bibliographically approved

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Olsson-Strömberg, Ulla

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