FAS Mutations Accelerate Lymphoma Growth and Induce Therapeutic Resistance
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».