Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response
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 progressi...
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| Format: | Article |
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eLife Sciences Publications Ltd
2024-11-01
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| Online Access: | https://elifesciences.org/articles/92074 |
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| author | Rebecca Warfvinge Linda Geironson Ulfsson Parashar Dhapola Fatemeh Safi Mikael Sommarin Shamit Soneji Henrik Hjorth-Hansen Satu Mustjoki Johan Richter Ram Krishna Thakur Göran Karlsson |
| author_facet | Rebecca Warfvinge Linda Geironson Ulfsson Parashar Dhapola Fatemeh Safi Mikael Sommarin Shamit Soneji Henrik Hjorth-Hansen Satu Mustjoki Johan Richter Ram Krishna Thakur Göran Karlsson |
| author_sort | Rebecca Warfvinge |
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| description | 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. |
| format | Article |
| id | doaj-art-d2afc990e3264278aae9d3f9ec4607bc |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-d2afc990e3264278aae9d3f9ec4607bc2025-08-20T02:12:34ZengeLife Sciences Publications LtdeLife2050-084X2024-11-011210.7554/eLife.92074Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy responseRebecca Warfvinge0Linda Geironson Ulfsson1Parashar Dhapola2Fatemeh Safi3Mikael Sommarin4Shamit Soneji5Henrik Hjorth-Hansen6https://orcid.org/0000-0002-2670-5696Satu Mustjoki7https://orcid.org/0000-0002-0816-8241Johan Richter8Ram Krishna Thakur9Göran Karlsson10https://orcid.org/0000-0001-8197-754XDivision of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, SwedenDivision of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, SwedenDivision of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, SwedenDivision of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, SwedenDivision of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, SwedenDivision of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, SwedenDepartment of Hematology, St Olavs Hospital, Trondheim, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, NorwayTranslational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland; Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Trondheim, Norway; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, FinlandDivision of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden; Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, SwedenDivision of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, SwedenDivision of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, SwedenThe 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.https://elifesciences.org/articles/92074leukemic stem cellCITE-SeqCMLCD26CD35BCR-ABL1 |
| spellingShingle | Rebecca Warfvinge Linda Geironson Ulfsson Parashar Dhapola Fatemeh Safi Mikael Sommarin Shamit Soneji Henrik Hjorth-Hansen Satu Mustjoki Johan Richter Ram Krishna Thakur Göran Karlsson Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response eLife leukemic stem cell CITE-Seq CML CD26 CD35 BCR-ABL1 |
| title | Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response |
| title_full | Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response |
| title_fullStr | Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response |
| title_full_unstemmed | Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response |
| title_short | Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response |
| title_sort | single cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response |
| topic | leukemic stem cell CITE-Seq CML CD26 CD35 BCR-ABL1 |
| url | https://elifesciences.org/articles/92074 |
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