Clonotype pattern in T-cell lymphomas map the cell of origin to immature lymphoid precursors
Bibliographic record
Abstract
Mature T-cell lymphomas (TCLs) are rare, clinically heterogeneous hematologic cancers with high medical need. TCLs have an inferior prognosis which is attributed to poor understanding of their pathogenesis. On the basis of phenotypic similarities between normal and neoplastic lymphocytes, it has been assumed that TCLs develop in the periphery, directly from various subtypes of normal T cells. To address the debated question of the cell of origin in TCLs, we attempted to identify the highly variable complementarity-determining regions (CDRs) of T-cell receptors (TCRs) to trace the clonal history of the T cells. We have collected previously published whole-genome, whole-exome, and whole-transcriptome sequencing data from 574 patients with TCL. TCR clonotypes were identified by de novo assembly of CDR3 regions of TCRα, TCRβ, and TCRγ. We have found that the vast majority of TCLs are clonotypically oligoclonal, although the pattern of oligoclonality varied. Anaplastic large-cell lymphoma was the most diverse comprising multiple clonotypes of TCRα, TCRβ, and TCRγ, whereas adult TCL or leukemia and peripheral TCLs often showed monoclonality for TCRβ and TCRγ but had diverse TCRα clonotypes. These patterns of rearrangements indicated that TCLs are initiated at the level of the lymphoid precursor. In keeping with this hypothesis, TCR rearrangements in TCLs resembled the pattern seen in the human thymus, which showed biased usage of V (variable) and J (joining) segments of high combinatorial probability resulting in recurrent public CDR3 sequences shared across unrelated patients and different clinical TCL entities. Clonotypically diverse initiating cells may seed target tissues that are then responsible for disease relapses after therapy.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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".