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Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response

Warfvinge, Rebecca LU ; Geironson Ulfsson, Linda LU ; Dhapola, Parashar LU ; Safi, Fatemeh LU ; Sommarin, Mikael LU ; Soneji, Shamit LU ; Hjorth-Hansen, Henrik ; Mustjoki, Satu ; Richter, Johan LU and Thakur, Ram Krishna LU , et al. (2024) In eLife 12.
Abstract

The advent of tyrosine kinase inhibitors (TKIs) as treatment of chronic myeloid leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI-insensitive leukemia stem cells (LSCs) persist in most patients even after years of treatment and are imperative for disease progression as well as recurrence during treatment-free remission (TFR). Here, we have generated high-resolution single-cell multiomics maps from CML patients at diagnosis, retrospectively stratified by BCR::ABL1IS (%) following 12 months of TKI therapy. Simultaneous measurement of global gene expression profiles together with >40 surface markers from the same cells revealed that each patient harbored a unique composition of stem and progenitor... (More)

The advent of tyrosine kinase inhibitors (TKIs) as treatment of chronic myeloid leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI-insensitive leukemia stem cells (LSCs) persist in most patients even after years of treatment and are imperative for disease progression as well as recurrence during treatment-free remission (TFR). Here, we have generated high-resolution single-cell multiomics maps from CML patients at diagnosis, retrospectively stratified by BCR::ABL1IS (%) following 12 months of TKI therapy. Simultaneous measurement of global gene expression profiles together with >40 surface markers from the same cells revealed that each patient harbored a unique composition of stem and progenitor cells at diagnosis. The patients with treatment failure after 12 months of therapy had a markedly higher abundance of molecularly defined primitive cells at diagnosis compared to the optimal responders. The multiomic feature landscape enabled visualization of the primitive fraction as a mixture of molecularly distinct BCR::ABL1+ LSCs and BCR::ABL1-hematopoietic stem cells (HSCs) in variable ratio across patients, and guided their prospective isolation by a combination of CD26 and CD35 cell surface markers. We for the first time show that BCR::ABL1+ LSCs and BCR::ABL1- HSCs can be distinctly separated as CD26+CD35- and CD26-CD35+, respectively. In addition, we found the ratio of LSC/HSC to be higher in patients with prospective treatment failure compared to optimal responders, at diagnosis as well as following 3 months of TKI therapy. Collectively, this data builds a framework for understanding therapy response and adapting treatment by devising strategies to extinguish or suppress TKI-insensitive LSCs.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy, Humans, Single-Cell Analysis/methods, Protein Kinase Inhibitors/pharmacology, Neoplastic Stem Cells/metabolism, Retrospective Studies, Male, Female, Gene Expression Profiling, Middle Aged, Multiomics
in
eLife
volume
12
publisher
eLife Sciences Publications
external identifiers
  • pmid:39503729
  • scopus:85208603370
ISSN
2050-084X
DOI
10.7554/eLife.92074
language
English
LU publication?
yes
additional info
© 2023, Warfvinge et al.
id
d6e13a5b-5786-4781-b112-b2cc39452fab
date added to LUP
2024-12-11 14:21:20
date last changed
2025-01-09 05:31:59
@article{d6e13a5b-5786-4781-b112-b2cc39452fab,
  abstract     = {{<p>The advent of tyrosine kinase inhibitors (TKIs) as treatment of chronic myeloid leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI-insensitive leukemia stem cells (LSCs) persist in most patients even after years of treatment and are imperative for disease progression as well as recurrence during treatment-free remission (TFR). Here, we have generated high-resolution single-cell multiomics maps from CML patients at diagnosis, retrospectively stratified by BCR::ABL1IS (%) following 12 months of TKI therapy. Simultaneous measurement of global gene expression profiles together with &gt;40 surface markers from the same cells revealed that each patient harbored a unique composition of stem and progenitor cells at diagnosis. The patients with treatment failure after 12 months of therapy had a markedly higher abundance of molecularly defined primitive cells at diagnosis compared to the optimal responders. The multiomic feature landscape enabled visualization of the primitive fraction as a mixture of molecularly distinct BCR::ABL1+ LSCs and BCR::ABL1-hematopoietic stem cells (HSCs) in variable ratio across patients, and guided their prospective isolation by a combination of CD26 and CD35 cell surface markers. We for the first time show that BCR::ABL1+ LSCs and BCR::ABL1- HSCs can be distinctly separated as CD26+CD35- and CD26-CD35+, respectively. In addition, we found the ratio of LSC/HSC to be higher in patients with prospective treatment failure compared to optimal responders, at diagnosis as well as following 3 months of TKI therapy. Collectively, this data builds a framework for understanding therapy response and adapting treatment by devising strategies to extinguish or suppress TKI-insensitive LSCs.</p>}},
  author       = {{Warfvinge, Rebecca and Geironson Ulfsson, Linda and Dhapola, Parashar and Safi, Fatemeh and Sommarin, Mikael and Soneji, Shamit and Hjorth-Hansen, Henrik and Mustjoki, Satu and Richter, Johan and Thakur, Ram Krishna and Karlsson, Göran}},
  issn         = {{2050-084X}},
  keywords     = {{Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy; Humans; Single-Cell Analysis/methods; Protein Kinase Inhibitors/pharmacology; Neoplastic Stem Cells/metabolism; Retrospective Studies; Male; Female; Gene Expression Profiling; Middle Aged; Multiomics}},
  language     = {{eng}},
  month        = {{11}},
  publisher    = {{eLife Sciences Publications}},
  series       = {{eLife}},
  title        = {{Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response}},
  url          = {{http://dx.doi.org/10.7554/eLife.92074}},
  doi          = {{10.7554/eLife.92074}},
  volume       = {{12}},
  year         = {{2024}},
}