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

## TL;DR

This study identifies a unique type of cancer cell in childhood T-cell leukemia that is linked to treatment resistance and poor outcomes.

## Contribution

The discovery of a transcriptionally distinct lymphoblast population associated with refractory T-ALL.

## Key findings

- A distinctive blast population resembling innate-like lymphocytes is the main source of refractory T-ALL.
- Evidence of these blasts at diagnosis predicts treatment resistance and poor survival in T-ALL patients.
- Refractory T-ALL is characterized as a distinct disease state with potential clinical implications.

## 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.

T-cell acute lymphoblastic leukemia is a highly aggressive disease with varying recurrence rates. Here, the authors build a single cell transcriptomic atlas of childhood T-cell acute lymphoblastic leukaemia (T-ALL). They identified a distinctive cancer cell state that correlates with high risk, treatment refractory T-ALL.