Molecular Pathogenesis of T Lymphoblastic Lymphomas in an Atm-deficient Mouse Model
Bibliographic record
Abstract
T lymphoblastic lymphoma/leukemia (T-LL) represent malignant disease of T-cell progenitors. Dysregulation of Notch1 and IL-7R pathways promotes T-LL, however the timing of these events remains unclear. Furthermore, the spectrum of Notch1 mutations has not been fully characterized in T-LL models. Chapter 2 demonstrated 3 T-LLs classified based on activated Notch1 (ICN1) expression that arose spontaneously in mice lacking ataxia telangiectasia mutated (ATM) protein. One group expressed truncated forms of ICN1 (T-ICN1) resulting from frame-shifting PEST mutations. T-LL cells but not normal thymocytes expressed a proteoglycan, syndecan 1 (SDC1). SDC1+ blasts were detected in thymi with normal cellularity from clinically healthy mice, thus representing the earliest discernible stage of T-LL progression. T-ICN1 and IL-7Rα were both aberrantly expressed at this early T-LL stage. Therefore, these data suggest that Notch1 mutations, aberrant expression of IL-7Rα and SDC1 arise early during T-LL progression. Chapter 3 demonstrated a paucity of HD mutations, yet T-LL cells proliferated in a Notch ligand-independent fashion. Analysis of ICN1+ T-LLs revealed truncated Notch1 mRNAs lacking ligand-binding domain and part of negative regulatory region. All truncated transcripts contained the intramembranous methionine that has previously been shown to serve as the translational start site. Collectively, our data identify truncated Notch1 mRNAs in T-LLs that likely encode for polypeptides undergoing ligand-independent activation. The third group lacked ICN1 expression (UD-ICN1). Chapter 4 revealed that UD-ICN1 T-LLs expressed low levels of Notch targets and proliferated independently of Notch signal. Gene set enrichment analyses of genes differentially expressed between UD-ICN1 and T-ICN1 T-LLs revealed higher levels of transcription factor krüppel-like factor 9 (Klf9) and other transcriptional regulators associated with the highly proliferative pre-DP stage of normal T-cell development. siRNA knockdown experiments demonstrated that Klf9 promoted proliferation of UD-ICN1 T-LL cells. Although further studies are warranted, the findings in this thesis reveal oncogenic activation of Notch1 as an early event in Atm-/- T-LL progression, and truncated Notch1 transcripts likely represent a novel mode of ligand-independent Notch1 activation. On the other hand, Klf9 promotes proliferation of Notch-independent T-LLs and may represent a potential therapeutic target for this T-LL group.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".