SOX11 Directly Represses Wnt/β-Catenin Signaling and Identifies a Subgroup of Mantle Cell Lymphoma Patients with Improved Survival with Intensive Treatment
Bibliographic record
Abstract
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.
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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 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 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".