Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia
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.
Authors
- Beat Bornhäuser (ORCID: https://orcid.org/0000-0003-2890-3191)
- Anna Mathioudaki (ORCID: https://orcid.org/0000-0003-4617-7015)
- Andreas E. Kulozik (ORCID: https://orcid.org/0000-0003-1953-0848)
- Tobias Rausch (ORCID: https://orcid.org/0000-0001-5773-5620)
- Judith B. Zaugg (ORCID: https://orcid.org/0000-0001-8324-4040)
- Jean‐Pierre Bourquin (ORCID: https://orcid.org/0000-0001-6571-6227)
- Martin Schrappe
- Jan O. Korbel (ORCID: https://orcid.org/0000-0002-2798-3794)
- Kerstin K. Rauwolf (ORCID: https://orcid.org/0000-0002-9778-0669)
- Cornelia Eckert (ORCID: https://orcid.org/0000-0003-1039-2872)
- Julia Costea (ORCID: https://orcid.org/0000-0001-7942-4495)
- Pietro Zafferani
- Gabriele Escherich (ORCID: https://orcid.org/0000-0003-3901-8745)
Institutions
- European Bioinformatics Institute (GB)
- European Molecular Biology Organization (DE)
- Universität Hamburg (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- University Hospital Schleswig-Holstein (DE)
- Hopp Children's Cancer Center Heidelberg (DE)
- University Children's Hospital Zurich (CH)
- European Molecular Biology Laboratory (DE)
- Charité - Universitätsmedizin Berlin (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1038/s41467-025-61222-1
- Citations
- 2
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 3.76
Funders
- Deutsche Krebshilfe
- Dr. Mildred Scheel Stiftung für Krebsforschung