Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia
Abstract T-ALL relapses are characterized by chemotherapy resistance, cellular diversity and dismal outcome. To gain a deeper understanding of the mechanisms underlying relapses, we conduct single-cell RNA sequencing on 13 matched pediatric T-ALL patient-derived samples at diagnosis and relapse, alo...
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| Format: | Article |
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61222-1 |
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| author | Julia Costea Kerstin K. Rauwolf Pietro Zafferani Tobias Rausch Anna Mathioudaki Judith Zaugg Martin Schrappe Cornelia Eckert Gabriele Escherich Jean P. Bourquin Beat Bornhauser Andreas E. Kulozik Jan O. Korbel |
| author_facet | Julia Costea Kerstin K. Rauwolf Pietro Zafferani Tobias Rausch Anna Mathioudaki Judith Zaugg Martin Schrappe Cornelia Eckert Gabriele Escherich Jean P. Bourquin Beat Bornhauser Andreas E. Kulozik Jan O. Korbel |
| author_sort | Julia Costea |
| collection | DOAJ |
| description | Abstract T-ALL relapses are characterized by chemotherapy resistance, cellular diversity and dismal outcome. To gain a deeper understanding of the mechanisms underlying relapses, we conduct single-cell RNA sequencing on 13 matched pediatric T-ALL patient-derived samples at diagnosis and relapse, along with samples derived from 5 non-relapsing patients collected at diagnosis. This comprehensive longitudinal single-cell study in T-ALL reveals significant transcriptomic diversity. Notably, 11 out of 18 samples exhibit a subpopulation of T-ALL cells with stem-like features characterized by a common set of active regulons, expression patterns and splice isoforms. This subpopulation, accounting for a small proportion of leukemia cells at diagnosis, expands substantially at relapse, indicating resistance to therapy. Strikingly, increased stemness at diagnosis is associated with higher risk of treatment induction failure. Chemotherapy resistance is validated through in-vitro and in-vivo drug testing. Thus, we report the discovery of treatment-resistant stem-like cells in T-ALL, underscoring the potential for devising future therapeutic strategies targeting stemness-related pathways. |
| format | Article |
| id | doaj-art-cfd383dc119b4f36a259ffce4d4851a1 |
| institution | Matheson Library |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-cfd383dc119b4f36a259ffce4d4851a12025-06-29T11:13:04ZengNature PortfolioNature Communications2041-17232025-06-0116111410.1038/s41467-025-61222-1Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemiaJulia Costea0Kerstin K. Rauwolf1Pietro Zafferani2Tobias Rausch3Anna Mathioudaki4Judith Zaugg5Martin Schrappe6Cornelia Eckert7Gabriele Escherich8Jean P. Bourquin9Beat Bornhauser10Andreas E. Kulozik11Jan O. Korbel12Molecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of Heidelberg UniversityDivision of Pediatric Oncology, University Children’s HospitalEuropean Molecular Biology Laboratory (EMBL), Genome Biology UnitMolecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of Heidelberg UniversityMolecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of Heidelberg UniversityMolecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of Heidelberg UniversityDepartment of Pediatrics, University Hospital Schleswig-Holstein, Campus KielDepartment of Pediatric Oncology/Hematology, Charité Universitätsmedizin BerlinClinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-EppendorfDivision of Pediatric Oncology, University Children’s HospitalDivision of Pediatric Oncology, University Children’s HospitalMolecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of Heidelberg UniversityMolecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of Heidelberg UniversityAbstract T-ALL relapses are characterized by chemotherapy resistance, cellular diversity and dismal outcome. To gain a deeper understanding of the mechanisms underlying relapses, we conduct single-cell RNA sequencing on 13 matched pediatric T-ALL patient-derived samples at diagnosis and relapse, along with samples derived from 5 non-relapsing patients collected at diagnosis. This comprehensive longitudinal single-cell study in T-ALL reveals significant transcriptomic diversity. Notably, 11 out of 18 samples exhibit a subpopulation of T-ALL cells with stem-like features characterized by a common set of active regulons, expression patterns and splice isoforms. This subpopulation, accounting for a small proportion of leukemia cells at diagnosis, expands substantially at relapse, indicating resistance to therapy. Strikingly, increased stemness at diagnosis is associated with higher risk of treatment induction failure. Chemotherapy resistance is validated through in-vitro and in-vivo drug testing. Thus, we report the discovery of treatment-resistant stem-like cells in T-ALL, underscoring the potential for devising future therapeutic strategies targeting stemness-related pathways.https://doi.org/10.1038/s41467-025-61222-1 |
| spellingShingle | Julia Costea Kerstin K. Rauwolf Pietro Zafferani Tobias Rausch Anna Mathioudaki Judith Zaugg Martin Schrappe Cornelia Eckert Gabriele Escherich Jean P. Bourquin Beat Bornhauser Andreas E. Kulozik Jan O. Korbel Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia Nature Communications |
| title | Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia |
| title_full | Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia |
| title_fullStr | Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia |
| title_full_unstemmed | Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia |
| title_short | Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia |
| title_sort | role of stem like cells in chemotherapy resistance and relapse in pediatric t cell acute lymphoblastic leukemia |
| url | https://doi.org/10.1038/s41467-025-61222-1 |
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