Journal Article

DKFZ-2025-01318

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia.

Costea, J. ; Rauwolf, K. K. ; Zafferani, P.DKFZ* ; Rausch, T. ; Mathioudaki, A.DKFZ* ; Zaugg, J. ; Schrappe, M. ; Eckert, C.DKFZ* ; Escherich, G. ; Bourquin, J. P. ; Bornhauser, B. ; Kulozik, A.DKFZ* ; Korbel, J. (Last author)DKFZ*

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-61222-1

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.

Keyword(s): Humans (MeSH) ; Drug Resistance, Neoplasm: genetics (MeSH) ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: drug therapy (MeSH) ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: genetics (MeSH) ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: pathology (MeSH) ; Child (MeSH) ; Neoplastic Stem Cells: metabolism (MeSH) ; Neoplastic Stem Cells: pathology (MeSH) ; Neoplastic Stem Cells: drug effects (MeSH) ; Single-Cell Analysis (MeSH) ; Male (MeSH) ; Female (MeSH) ; Child, Preschool (MeSH) ; Adolescent (MeSH) ; Neoplasm Recurrence, Local: genetics (MeSH) ; Recurrence (MeSH) ; Transcriptome (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Cell Line, Tumor (MeSH) ; Gene Expression Regulation, Leukemic (MeSH)

Note: #LA:B480#

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Contributing Institute(s):

1. B270 Regulatorische Genomik und Evolution von Tumoren (B270)
2. Künstl. Intelligenz in der Onkologie (B450)
3. DKTK Koordinierungsstelle Berlin (BE01)
4. KKE Pädiatrische Leukämie (A400)
5. Mechanismen der genetischen Variation und Datenwissenschaft (B480)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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