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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.

journal_name

Blood

journal_title

Blood

authors

Warfvinge R,Geironson L,Sommarin MNE,Lang S,Karlsson C,Roschupkina T,Stenke L,Stentoft J,Olsson-Strömberg U,Hjorth-Hansen H,Mustjoki S,Soneji S,Richter J,Karlsson G

doi

10.1182/blood-2016-07-728873

subject

Has Abstract

pub_date

2017-04-27 00:00:00

pages

2384-2394

issue

17

eissn

0006-4971

issn

1528-0020

pii

blood-2016-07-728873

journal_volume

129

pub_type

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