SOX11 Directly Represses Wnt/β-Catenin Signaling and Identifies a Subgroup of Mantle Cell Lymphoma Patients with Improved Survival with Intensive Treatment
Notice bibliographique
Résumé
Abstract Abstract 895 The SOX11 (Sex determining region Y)-box 11 transcription factor is aberrantly expressed in the majority (78-93%) of Mantle Cell Lymphoma (MCL) patients. Functionally, SOX11 represses MCL cell proliferation in vitro. We identify SOX11 mediated repression of Wnt signaling as contributory to the proliferation block in vitro and determine the clinical consequences of SOX11 overexpression in a meta-analysis of 3 large international patient cohorts. We have previously identified SOX11 direct binding target genes using chromatin immunoprecipitation coupled with high resolution, next generation sequencing (ChIP-Seq). Members of the Wnt signaling pathway, which is known to promote proliferation in MCL, were significantly enriched in our ChIP analysis in MCL patients and cell lines. Using a luciferase reporter assay for nuclear beta-catenin activity, we find that overexpression of SOX11 represses Wnt signaling (p<0.005) in vitro in Z138 and JEKO-1 cells. Conversely, depletion of SOX11 using siRNA increased Wnt signaling (p<0.05) in the same cell lines. The overexpression phenotype is characterized by G2/M arrest and proliferation block in five MCL cell lines studied, irrespective of p53 status or endogenous SOX11 levels. The relationship between SOX11 and proliferation was validated in primary patient samples. Interrogation of an eighty-two patient gene-expression dataset demonstrates that SOX11 mRNA expression is significantly (p<0.05) and inversely proportional to Ki-67, a marker of cell proliferation. Similarly, expression of SOX11 is inversely proportional to beta-catenin (p<0.05) supporting our in vitro data showing crosstalk between SOX11 and Wnt pathways in SOX11 mediated repression of cell proliferation in MCL. Prior studies examining the impact of SOX11 expression on patient outcomes using immunohistochemistry have been hampered by small numbers and heterogeneity in treatment. To overcome patient selection and treatment biases, we analyzed SOX11 expression in a total of 386 patients from three independent well-annotated tissue microarrays from University of Wisconsin, Karolinska Institute and British Columbia Cancer Agency. Higher SOX11 expression was associated with improved overall survival (p<0.03) in patients treated with intensive regimens such as R-Hyper-CVAD or VCR-CVAD, independent of IPI/MIPI or p53 overexpression in these patients and similar to reports in epithelial malignancies. Conversely, there was no significant impact of SOX11 expression on survival in R-CHOP treated patients. In conclusion, building from our previous ChIP-seq data, we further validated the inverse association between SOX11 and proliferation in primary patient samples. Our functional data showing direct repression of Wnt signaling represents one pathway through which SOX11 can exert its anti-proliferative effect. Our meta-analysis indicates that higher SOX11 expression is associated with improved survival in MCL patients treated with intensive chemotherapy. This supports prospective validation of SOX11 as a bioassay to select patients more likely to benefit from intensive therapy in MCL. Transcriptional regulation of Wnt and other biological pathways affected by SOX11 target genes help explain the impact of SOX11 expression on patient outcomes. Disclosures: Goy: Milennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; J & J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 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 ».