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Lookup NU author(s): Dr Laura JardineORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025. Refractory cancers may arise either through the acquisition of resistance mechanisms or represent distinct disease states. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we perform single cell mRNA sequencing of T-ALL from 58 children (84 samples) who did, or did not respond to initial treatment. We identify a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease. Evidence of such blasts at diagnosis heralds refractory disease across independent datasets and is associated with survival in a large, contemporary trial cohort. Our findings portray refractory T-ALL as a distinct disease with the potential for immediate clinical utility.
Author(s): Lim BSJ, Whitfield HJ, Trinh MK, Bloye G, Thomas R, Anderson ND, Wenger A, Hodder A, Treger TD, Lee-Six H, Coorens THH, Parks C, Ogbonnah T, Polonen P, Mullighan CG, Teachey DT, Xu J, Tan K, Hagleitner M, Kester L, van Leeuwen FN, Beattie G, Mansour MR, Williams O, Bartram J, Adams S, Jardine L, Behjati S, O'Connor D
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2025
Volume: 16
Online publication date: 12/11/2025
Acceptance date: 01/10/2025
Date deposited: 27/11/2025
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-025-65049-8
DOI: 10.1038/s41467-025-65049-8
Data Access Statement: Raw sequencing data (DNA, bulk mRNA and single cell mRNA) are available through the European Genome-Phenome Archive (EGA) under the following accession codes: EGAD00001009058 (DNA and bulk mRNA sequencing of discovery cohort), EGAD50000001128 (bulk mRNA and single cell mRNA sequencing of discovery cohort), EGAD00001015727 (DNA sequencing of validation cohort, as well as day 28 samples for P058 and P030), and EGAD00001015673 (single cell mRNA sequencing of validation cohort). Data on EGA are accessible on application to the EGA website (https://ega-archive.org/). Processed and raw gene expression counts for single-cell mRNA sequencing of the discovery and validation cohorts are freely available on the CellxGene repository (https://cellxgene.cziscience.com/collections/962df42d-9675-4d05-bc75-597ec7bf4afb). [Please see the article for the full Data Access Statement.]
PubMed id: 41224801
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