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Insights from Single-cell Omics - Cellular Heterogeneity as a Foundation of Clinical Outcome in Chronic Myeloid Leukemia

Thakur, Ram Krishna LU and Karlsson, Göran LU (2025) In Blood
Abstract

The BCR::ABL1 tyrosine kinase inhibitors (TKIs) in CML represent a paradigm for molecularly targeted therapy. However, clinical outcomes - rate/depth of response, treatment-free remission (TFR), progression to blast crisis (BC) - and adverse events vary among patients. While additional somatic mutations have been invoked to explain varying clinical outcomes, we here propose a complementary perspective based on single-cell omics approaches that have enabled unprecedented resolution of the cellular ecosystems, including their composition, interactions, and activity. In treatment-naïve chronic phase (CP) patients, this has revealed differences in the growth-rate of BCR::ABL1+ clones, ratio of TKI-insensitive leukemic stem cells (LSCs) to... (More)

The BCR::ABL1 tyrosine kinase inhibitors (TKIs) in CML represent a paradigm for molecularly targeted therapy. However, clinical outcomes - rate/depth of response, treatment-free remission (TFR), progression to blast crisis (BC) - and adverse events vary among patients. While additional somatic mutations have been invoked to explain varying clinical outcomes, we here propose a complementary perspective based on single-cell omics approaches that have enabled unprecedented resolution of the cellular ecosystems, including their composition, interactions, and activity. In treatment-naïve chronic phase (CP) patients, this has revealed differences in the growth-rate of BCR::ABL1+ clones, ratio of TKI-insensitive leukemic stem cells (LSCs) to residual hematopoietic stem cells (HSCs), and immune cell composition - factors that collectively contribute to variability in therapy efficacy. Together these findings suggest that cellular heterogeneity serves as a foundation of clinical outcome in CML. Patients who remain in CP exhibit an erythroid signature in LSCs, while those progressing to BC manifest an inflammatory profile, additional mutations, and expansion of early progenitors. Deep responders with active natural killer, and regulatory T-cells are more likely to sustain TFR. Similarly, the outcomes of donor lymphocyte infusion after allogenic stem cell transplantation are heterogenous and reflect differences in pre-existing T-cell clonotypes, their expansion and interaction with leukemic cells in responders versus non-responders. Here, we summarize key insights from sc-omics in CML and propose an actionable roadmap to further leverage these technologies. This includes mechanistically explaining heterogeneity, predicting therapy response and BC, tracking leukemogenic clones longitudinally, targeting TKI-insensitive LSCs, and restoring hematopoiesis from residual HSCs.

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author
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organization
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type
Contribution to journal
publication status
epub
subject
in
Blood
publisher
American Society of Hematology
external identifiers
  • pmid:41105914
ISSN
1528-0020
DOI
10.1182/blood.2025029011
language
English
LU publication?
yes
additional info
Copyright © 2025 American Society of Hematology.
id
d9955bcf-aae5-4f48-b07a-7f6040b437af
date added to LUP
2025-11-10 10:03:40
date last changed
2025-11-10 13:35:44
@article{d9955bcf-aae5-4f48-b07a-7f6040b437af,
  abstract     = {{<p>The BCR::ABL1 tyrosine kinase inhibitors (TKIs) in CML represent a paradigm for molecularly targeted therapy. However, clinical outcomes - rate/depth of response, treatment-free remission (TFR), progression to blast crisis (BC) - and adverse events vary among patients. While additional somatic mutations have been invoked to explain varying clinical outcomes, we here propose a complementary perspective based on single-cell omics approaches that have enabled unprecedented resolution of the cellular ecosystems, including their composition, interactions, and activity. In treatment-naïve chronic phase (CP) patients, this has revealed differences in the growth-rate of BCR::ABL1+ clones, ratio of TKI-insensitive leukemic stem cells (LSCs) to residual hematopoietic stem cells (HSCs), and immune cell composition - factors that collectively contribute to variability in therapy efficacy. Together these findings suggest that cellular heterogeneity serves as a foundation of clinical outcome in CML. Patients who remain in CP exhibit an erythroid signature in LSCs, while those progressing to BC manifest an inflammatory profile, additional mutations, and expansion of early progenitors. Deep responders with active natural killer, and regulatory T-cells are more likely to sustain TFR. Similarly, the outcomes of donor lymphocyte infusion after allogenic stem cell transplantation are heterogenous and reflect differences in pre-existing T-cell clonotypes, their expansion and interaction with leukemic cells in responders versus non-responders. Here, we summarize key insights from sc-omics in CML and propose an actionable roadmap to further leverage these technologies. This includes mechanistically explaining heterogeneity, predicting therapy response and BC, tracking leukemogenic clones longitudinally, targeting TKI-insensitive LSCs, and restoring hematopoiesis from residual HSCs.</p>}},
  author       = {{Thakur, Ram Krishna and Karlsson, Göran}},
  issn         = {{1528-0020}},
  language     = {{eng}},
  month        = {{10}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{Insights from Single-cell Omics - Cellular Heterogeneity as a Foundation of Clinical Outcome in Chronic Myeloid Leukemia}},
  url          = {{http://dx.doi.org/10.1182/blood.2025029011}},
  doi          = {{10.1182/blood.2025029011}},
  year         = {{2025}},
}