Abstract A025 Single cell transcriptomics reveals a non-canonical lymphoblast in refractory childhood T cell leukaemia
Bibliographic record
Abstract
Abstract Paediatric T-cell acute lymphoblastic leukaemia (T-ALL) is a T cell malignancy for which there currently is no feature that reliably risk-stratifies patients at the point of diagnosis. The earliest reliable indicator of high-risk T-ALL is the presence of residual disease (≥ 5% cancer cells) after four weeks of induction chemotherapy. Various diagnostic biomarkers have been proposed to identify children with a poor prognosis, however, none have been sufficiently robust to enter clinical practice. We used single-cell RNA-sequencing to profile bone marrow aspirates both at diagnosis and after induction failure (at day 28) for 13 refractory patients, as well as 8 children who were responsive to chemotherapy. This high-resolution phenotyping allowed us to identify a ZBTB16+ cancer cell (blast) population that is present only in the diagnostic samples of induction failure patients and dominates their day 28 bone marrows. Comparison with normal immune cells revealed a strong similarity to unconventional innate-like lymphoid cells, indicating ZBTB16+ blasts represent a non-canonical, previously unrecognised, lymphoblast. To examine the clinical significance of ZBTB16+ blasts in large and publicly available bulk RNA-seq cohorts, we derived a 29-gene module that represents the ZBTB16+ non-canonical cell state. Using independent bulk RNA-seq cohorts for validation, we show that our gene module segregates patients who experience induction failure, independent of ETP status. Importantly, we show that ZBTB16+ blasts can be detected at the point of diagnosis and can be measured by intracellular flow cytometry, which can easily be incorporated into diagnostic panels. For one particular child, our index case, ZBTB16+ blasts were a minority population at diagnosis but dramatically expanded during induction treatment. We performed whole genome sequencing on the diagnostic, post-induction, and remission bone marrow of this child to investigate the phylogenetic relation of treatment-resistant ZBTB16+ blasts and sensitive ZBTB16- blasts that disappeared during induction. Using single nucleotide variants and copy number changes, we determined that ZBTB16+ blasts did not derive from diagnostic (treatment sensitive ZBTB16-) blasts. Our findings suggest that treatment-resistant blasts represent a distinct cancer cell state, rather than a clone that derives from the initial diagnostic population, which has the potential to transform risk stratification in T-ALL and offers a novel therapuetic target. Citation Format: Holly J. Whitfield, Bram Lim, Mi Trinh, Angus Hodder, Petri Polonen, David Teachy, Charles Mullighan, Melanie M. Hagleitner, Lennart Kester, Frank van Leeuwen, Jack Bartram, Owen Williams, Nathaniel D. Anderson, Laura Jardine, Sam Behjati, David O'Connor. Single cell transcriptomics reveals a non-canonical lymphoblast in refractory childhood T cell leukaemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A025.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".