A non-canonical lymphoblast in refractory childhood T-cell leukaemia

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.

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Publication Details

Journal
Nature Communications
Published
2025-11-12
DOI
https://doi.org/10.1038/s41467-025-65049-8
Primary Topic
Acute Lymphoblastic Leukemia research
Type
article
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article

A non-canonical lymphoblast in refractory childhood T-cell leukaemia

Kai Tan, Owen Williams, Gordon Beattie, Mi K. Trinh et al.
Nature Communications
Acute Lymphoblastic Leukemia research
article

A non-canonical lymphoblast in refractory childhood T-cell leukaemia

Kai Tan, Owen Williams, Gordon Beattie, Mi K. Trinh, Jason Xu, Jack Luke Bartram, Angus Hodder, Rebecca Thomas, Holly J. Whitfield, David T. Teachey, Petri Pölönen, Henry Lee-Six, Frank N. van Leeuwen, Gianna Bloye, Bram Lim, Melanie M. Hagleitner, Charles Grenfell Mullighan, Stuart Adams, Tim Coorens, Anna Wenger, Sam Behjati, David O’Connor, Marc R. Mansour, Lennart A. Kester, Laura Jardine, Taryn D. Treger, Nathaniel D. Anderson, Conor Parks, Toochi Ogbonnah
article en

Abstract

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.

Nature CommunicationsVol. 16(1)
Broad Institute (US), St. Jude Children's Research Hospital (US), Children's Hospital of Philadelphia (US), University of Cambridge (GB), Great Ormond Street Hospital (GB), Cancer Research UK (GB), Cambridge University Hospitals NHS Foundation Trust (GB), Wellcome Sanger Institute (GB), Princess Máxima Center (NL), CRUK Lung Cancer Centre of Excellence (GB), University College London (GB), University of Pennsylvania (US), Newcastle University (GB)
Openalex Percentile: Top 56%
Acute Lymphoblastic Leukemia research
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