TY  - JOUR
AU  - Costea, Julia
AU  - Rauwolf, Kerstin K
AU  - Zafferani, Pietro
AU  - Rausch, Tobias
AU  - Mathioudaki, Anna
AU  - Zaugg, Judith
AU  - Schrappe, Martin
AU  - Eckert, Cornelia
AU  - Escherich, Gabriele
AU  - Bourquin, Jean P
AU  - Bornhauser, Beat
AU  - Kulozik, Andreas
AU  - Korbel, Jan
TI  - Role of stem-like cells in chemotherapy resistance and relapse in pediatric T-cell acute lymphoblastic leukemia.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-01318
SP  - 5413
PY  - 2025
N1  - #LA:B480#
AB  - 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.
KW  - Humans
KW  - Drug Resistance, Neoplasm: genetics
KW  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: drug therapy
KW  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: genetics
KW  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: pathology
KW  - Child
KW  - Neoplastic Stem Cells: metabolism
KW  - Neoplastic Stem Cells: pathology
KW  - Neoplastic Stem Cells: drug effects
KW  - Single-Cell Analysis
KW  - Male
KW  - Female
KW  - Child, Preschool
KW  - Adolescent
KW  - Neoplasm Recurrence, Local: genetics
KW  - Recurrence
KW  - Transcriptome
KW  - Animals
KW  - Mice
KW  - Cell Line, Tumor
KW  - Gene Expression Regulation, Leukemic
LB  - PUB:(DE-HGF)16
C6  - pmid:40579412
DO  - DOI:10.1038/s41467-025-61222-1
UR  - https://inrepo02.dkfz.de/record/302323
ER  -