Lim, Bram SJ;
Whitfield, Holly J;
Trinh, Mi K;
Bloye, Gianna;
Thomas, Rebecca;
Anderson, Nathaniel D;
Wenger, Anna;
... O'connor, David; + view all
(2025)
A non-canonical lymphoblast in refractory childhood T-cell leukaemia.
Nature Communications
, 16
(1)
, Article 9397. 10.1038/s41467-025-65049-8.
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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.
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