FAS Mutations Accelerate Lymphoma Growth and Induce Therapeutic Resistance
Bibliographic record
Abstract
Abstract BACKGROUND: Rituximab-based chemotherapy is effective in inducing remissions in ~85% patients with untreated follicular lymphoma (FL). Primary treatment failure or an early relapse after first-line therapy is associated with a very poor prognosis. Recent sequencing efforts have been successful at identifying recurrent genetic events that contribute to the pathogenesis of FL, but the clinical significance of most of these events, in particular those contributing to therapeutic resistance, remain unknown. We identified a mutation in FAS (Y232*) in a patient with primary-refractory FL. FAS, a key death receptor in the extrinsic apoptotic pathway, plays a fundamental role in immune homeostasis by initiating apoptosis in lymphocytes once activated by FAS ligand (FASL) from neighboring cells. Herein, we show that mutations in FAS contribute to therapeutic resistance in FL. METHODS: We determined the incidence and clinical significance of FAS mutations in an extended cohort of 214 clinically-annotated FL biopsies. We determined the impact of the recurrent FAS(Y232*) mutation on FAS-mediated and chemotherapy-induced apoptosis in lymphoma cell lines. We measured the change in FAS and FASL expression in primary human T and B lymphocytes after exposure to chemotherapy. Finally, we cloned the murine equivalent of FAS(Y232*), Fas(Y224*), in Eu-Myc lymphoma cells and determined its effect on lymphoma growth and response to chemotherapy in immunocompetent C57BL/6 mice (n=36). RESULTS: FAS mutations were identified in 6% of FL patients. Coding FAS mutations were associated with a trend towards an earlier median time to progression (1 y versus 2.8 y, p=0.08) and an increased risk of histological transformation (p=0.036). The recurrent FAS(Y232*) mutation inhibited FAS-mediated apoptosis in cell lines but, unexpectedly, did not inhibit chemotherapy-mediated apoptosis. We hypothesized that in patients, chemotherapy induced a FAS-mediated immune response that was not modeled in vitro. Supporting this concept, we observed an increase in FASL and FAS expression on normal T and B lymphocytes, respectively, after exposure to etoposide. We injected three groups of mice with Eu-Myc lymphoma cells that differed only in their Fas genotype (Fas WT, Fas(Y224*) and an empty vector control) and monitored lymph node volumes before and after therapy. Fas(Y224*) dramatically accelerated lymphoma growth. Lymph node volumes exceeded those measured in Fas wild-type and control mice at all time points beyond the day of injection. The average maximal lymph node volume for the Fas(Y224*) group was 59.9 mm3 compared to 18.9 mm3 and 34.5 mm3 for the Fas WT and control groups, respectively (p < 0.001). Fas mutant lymphomas had an inferior response to doxorubicin and none of the mice in this group achieved a complete remission. Remarkably, the opposite phenotype was observed in the Fas WT group, where the addition of Fas WT inhibited lymphoma growth and induced earlier remissions. CONCLUSION: Mutations in FAS can be clinically important in patients with FL by promoting lymphoma growth and inducing therapeutic resistance. The full malignant phenotype of FAS mutant lymphomas could only be elicited in vivo, and not in vitro, suggesting that a FAS-mediated immune response controls lymphoma growth and actively participates in chemotherapy-induced cell death. Disclosures Connors: Seattle Genetics, Inc.: Research Funding; Roche: Research Funding.
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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) | 0.000 | 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) | 0.002 | 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 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".