A non-canonical lymphoblast in refractory childhood T-cell leukaemia
- Bram S. J. Lim
- Holly J. Whitfield
- Mi K. Trinh
- Gianna Bloye
- Rebecca Thomas
- Nathaniel D. Anderson
- Anna Wenger
- Angus Hodder
- Taryn D. Treger
- Henry Lee-Six
- Tim H. H. Coorens
- Conor Parks
- Toochi Ogbonnah
- Petri Pölönen
- Charles G. Mullighan
- David T. Teachey
- Jason Xu
- Kai Tan
- Melanie Hagleitner
- Lennart Kester
- Frank N. van Leeuwen
- Gordon Beattie
- Marc R. Mansour
- Owen Williams
- Jack Bartram
- Stuart Adams
- Laura Jardine
- Sam Behjati
- David O’Connor
2025-11-12
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.