SOX11, CD70, and Treg cells configure the tumor-immune microenvironment of aggressive mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a heterogeneous clinical and biological behavior. SOX11 oncogenic expression contributes to the aggressiveness of these tumors by different mechanisms, including tumor and stromal cell interactions. However, the precise composition of the immune cell microenvironment of MCL, its possible relationship to SOX11 expression, and how it may contribute to tumor behavior is not well known. Here, we performed an integrative transcriptome analysis of 730 immune-related genes combined with the immune cell phenotype analysis by immunohistochemistry in SOX11+ and SOX11- primary nodal MCL cases and non-neoplastic reactive lymph nodes. SOX11+ MCL had a significant lower T-cell intratumoral infiltration compared with negative cases. A reduced expression of MHCI/II-like and T-cell costimulation and signaling activation related transcripts was significantly associated with poor clinical outcome. Moreover, we identified CD70 as a SOX11 direct target gene, whose overexpression was induced in SOX11+, but not SOX11- tumor cells by CD40L in vitro. CD70 was overexpressed in primary SOX11+ MCL and it was associated with an immune unbalance of the tumor microenvironment characterized by increased number of effector regulatory t (Treg) cell infiltration, higher proliferation, and aggressive clinical course. CD27 was expressed with moderate to strong intensity in 76% of cases. Overall, our results suggest that SOX11 expression in MCL is associated with an immunosuppressive microenvironment characterized by CD70 overexpression in tumor cells, increased Treg cell infiltration and downmodulation of antigen processing, and presentation and T-cell activation that could promote MCL progression and represent a potential target for tailored therapies.

Single nucleotide variants in immune-response genes and the tumor microenvironment composition predict progression of mantle cell lymphoma.

BACKGROUND: There is evidence to consider that the tumor microenvironment (TME) composition associates with antitumor immune response, and may predict the outcome of various non-Hodgkin lymphoma subtypes. However, in the case of mantle cell lymphoma (MCL), a rare and aggressive disease, there is lacking a detailed study of the TME components, as well as an integrative approach among them in patients' samples. Also, from the genetic point of view, it is known that single nucleotide variants (SNVs) in immune-response genes are among important regulators of immunity. At present, it is uncertain whether SNVs in candidate immune-response genes and the TME composition are able to alter the prognosis in MCL. METHODS: We assessed a detailed TME composition in 88 MCL biopsies using immunohistochemistry, which was automatically analyzed by pixel counting (Aperio system). We also genotyped SNVs located in candidate immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, IL17F) in 95 MCL patients. We tested whether the SNVs could modulate the respective protein expression and TME composition in the tumor compartment. Finally, we proposed survival models in rituximab-treated patients, considering immunohistochemical and SNV models. RESULTS: High FOXP3/CD3 ratios (p = 0.001), high IL17A levels (p = 0.003) and low IL2 levels (p = 0.03) were individual immunohistochemical predictors of poorer survival. A principal component, comprising high quantities of macrophages and high Ki-67 index, also worsened outcome (p = 0.02). In the SNV model, the CC haplotype of IL10 (p < 0.01), the GG genotype of IL2 rs2069762 (p = 0.02) and the AA+AG genotypes of TGFBR2 rs3087465 (p < 0.01) were independent predictors of outcome. Finally, the GG genotype of TGFB1 rs6957 associated with lower tumor TGFß levels (p = 0.03) and less CD163+ macrophages (p = 0.01), but did not modulate patients' survival. CONCLUSIONS: Our results indicate that the TME composition has relevant biological roles in MCL. In this setting, immunohistochemical detection of T-reg cells, IL17A and IL2, coupled with SNV genotyping in IL10, TGFBR2 and IL2, may represent novel prognostic factors in this disease, following future validations.

Immunophenotypic Characterization of Germ Cell Tumor-Derived Primitive Neuroectodermal Tumors: Evidence for Frequent Neuronal and/or Glial Differentiation.

CONTEXT.­: Primitive neuroectodermal tumors (PNETs) may arise as a somatic-type malignancy in germ cell tumors. In this setting, most PNETs resemble those of the central nervous system and lack chromosome 22 translocations. However, description of the morphologic and differentiation spectrum of PNETs arising from germ cell tumors is lacking. OBJECTIVE.­: To investigate the morphologic and immunohistochemical features of these tumors, concentrating on neuronal and glial features. DESIGN.­: We selected cases based on a morphologically identifiable glial and/or differentiated neuronal component in association with the undifferentiated PNET. Immunohistochemistry for glial fibrillary acidic protein, S100 protein, synaptophysin, chromogranin A, and SOX11 was performed on tumors with available material, with the scoring of both staining intensity (0-3) and extent (0-3). Thirteen qualifying PNETs of testicular origin with available immunohistochemical stains or stainable material were identified. The complete stain panel was performed in 10 tumors. RESULTS.­: SOX11 demonstrated positive staining in the undifferentiated PNET component of all tumors (10 of 10) and was rarely positive in the differentiated (ie, neuronal/glial) component (1 of 10; focal and weak); synaptophysin was slightly less sensitive in the undifferentiated component (12 of 13; often focal and weak) and also showed positivity in the neuronal/glial component (5 of 13). Glial fibrillary acidic protein and S100 were more frequently positive in the differentiated areas (83% and 77%, respectively) compared with undifferentiated areas (25% and 17%, respectively). CONCLUSIONS.­: SOX11 is a sensitive immunohistochemical marker for testicular PNET, particularly those lacking differentiation. Testicular PNETs often demonstrate glial and/or neuronal differentiation. Differentiation is marked by the acquisition of S100 and glial fibrillary acidic protein expression and SOX11 loss.

SOX11-negative Mantle Cell Lymphoma: Clinicopathologic and Prognostic Features of 75 Patients.

Studies have suggested that SOX11 expression has prognostic implications in patients with mantle cell lymphoma (MCL), but the data are controversial. In this study, we describe the clinicopathologic and prognostic features of 75 patients with SOX11-negative MCL. Compared with patients with SOX11-positive MCL, SOX11-negative MCL patients more frequently had leukemic non-nodal disease (21% vs. 4%, P=0.0001). SOX11-negative MCLs more often showed classic morphology (83% vs. 65%, P=0.005), were more often positive for CD23 (39% vs. 22%, P=0.02) and CD200 (60% vs. 9%, P=0.0001), and had a lower proliferation index (Ki67 23% vs. 33%, P=0.04). Overall survival (OS) was not significantly different between patients with SOX11-negative versus SOX11-positive MCL (P=0.63). High Ki67 index and blastoid/pleomorphic morphology were associated with shorter OS in both SOX11-negative (P<0.05) and SOX11-positive MCL groups (P<0.05). A high Mantle Cell Lymphoma International Prognostic Index (MIPI) predicted poorer prognosis in patients with SOX11-negative MCL (P<0.0001), but not SOX11-positive MCL (P=0.09). Nodal involvement and stage III/IV disease were associated with poorer outcome in patients with SOX11-positive MCL (P=0.03 and 0.04, respectively), but not SOX11-negative MCL (P=0.88 and 0.74, respectively). In summary, SOX11-negative MCL is characterized by more frequent leukemic non-nodal disease, classic morphology, more frequent expression of CD23 and CD200, and a lower Ki67 index. Prognostic factors in patients with SOX11-negative MCL include morphology, Ki67 index, and MIPI score.

SOX11: a potentially useful marker in surgical pathology: a systematic analysis of SOX11 expression in epithelial and non-epithelial tumours.

AIMS: SOX11 is known as an essential transcription factor for regulating neurogenesis. Recently, SOX11 has been suggested to be a diagnostic marker and oncogene because of its significant expression in mantle cell lymphoma (MCL). However, SOX11 expression in other tumour types has not yet been extensively studied. METHODS AND RESULTS: Herein, we examined SOX11 expression in 2026 cases of neuroectodermal, germ cell, mesenchymal and epithelial tumours by immunohistochemistry. SOX11 was consistently expressed in all neuroectodermal tumours with neural differentiation, as well as in immature teratomas revealing neurogenesis. Less frequently, SOX11 expression was observed in only 50% of astrocytomas and 24% of malignant peripheral nerve sheath tumours, and was mainly sporadic and weak/intermediate. In epithelial tumours, significant SOX11 expression was identified in 97% of salivary ductal carcinomas (SDCs) and a high percentage of high-grade neuroendocrine carcinomas (NECs), especially the small-cell lung carcinomas (68%), and was absent in most other carcinomas, except for less and/or focal and weak expression in adenocarcinomas from the lung, genital tract and breast, and salivary adenoid cystic carcinomas and epithelial-myoepithelial carcinomas. In mesenchymal tumours, in addition to MCLs, prominent SOX11 expression was observed in 90% of rhabdomyosarcomas and all myxoid/round cell liposarcomas (MRCLs). Less frequent and/or focal and weak expression was observed in lymphoblastic, Burkitt and follicular lymphomas, synovial sarcoma and angiosarcoma. CONCLUSION: SOX11 showed prominent expression in neuroectodermal tumours with neural differentiation, high grade-NEC, SDC, rhabdomyosarcoma and MRCL. The high sensitivity and specificity of SOX11 in SDC and MRCL make it a useful diagnostic marker.

Sox4 Promotes Atoh1-Independent Intestinal Secretory Differentiation Toward Tuft and Enteroendocrine Fates.

BACKGROUND & AIMS: The intestinal epithelium is maintained by intestinal stem cells (ISCs), which produce postmitotic absorptive and secretory epithelial cells. Initial fate specification toward enteroendocrine, goblet, and Paneth cell lineages requires the transcription factor Atoh1, which regulates differentiation of the secretory cell lineage. However, less is known about the origin of tuft cells, which participate in type II immune responses to parasite infections and appear to differentiate independently of Atoh1. We investigated the role of Sox4 in ISC differentiation. METHODS: We performed experiments in mice with intestinal epithelial-specific disruption of Sox4 (Sox4fl/fl:vilCre; SOX4 conditional knockout [cKO]) and mice without disruption of Sox4 (control mice). Crypt- and single-cell-derived organoids were used in assays to measure proliferation and ISC potency. Lineage allocation and gene expression changes were studied by immunofluorescence, real-time quantitative polymerase chain reaction, and RNA-seq analyses. Intestinal organoids were incubated with the type 2 cytokine interleukin 13 and gene expression was analyzed. Mice were infected with the helminth Nippostrongylus brasiliensis and intestinal tissues were collected 7 days later for analysis. Intestinal tissues collected from mice that express green fluorescent protein regulated by the Atoh1 promoter (Atoh1GFP mice) and single-cell RNA-seq analysis were used to identify cells that coexpress Sox4 and Atoh1. We generated SOX4-inducible intestinal organoids derived from Atoh1fl/fl:vilCreER (ATOH1 inducible knockout) mice and assessed differentiation. RESULTS: Sox4cKO mice had impaired ISC function and secretory differentiation, resulting in decreased numbers of tuft and enteroendocrine cells. In control mice, numbers of SOX4+ cells increased significantly after helminth infection, coincident with tuft cell hyperplasia. Sox4 was activated by interleukin 13 in control organoids; SOX4cKO mice had impaired tuft cell hyperplasia and parasite clearance after infection with helminths. In single-cell RNA-seq analysis, Sox4+/Atoh1- cells were enriched for ISC, progenitor, and tuft cell genes; 12.5% of Sox4-expressing cells coexpressed Atoh1 and were enriched for enteroendocrine genes. In organoids, overexpression of Sox4 was sufficient to induce differentiation of tuft and enteroendocrine cells-even in the absence of Atoh1. CONCLUSIONS: We found Sox4 promoted tuft and enteroendocrine cell lineage allocation independently of Atoh1. These results challenge the longstanding model in which Atoh1 is the sole regulator of secretory differentiation in the intestine and are relevant for understanding epithelial responses to parasitic infection.

Association of SOX11 gene expression withclinical features and prognosis of mantle cell lymphoma.

OBJECTIVE: To study the expression of SOX11 in the patients with mantle cell lymphoma (MCL) and explore the clinical values of SOX11 in MCL. PATIENTS AND METHODS: In the paraffin-embedded MCL tissues of 75 patients diagnosed in the Department of Hematology, Shanxi Tumor Hospital, were performed the immunohistochemical labeling of Ki67 and SOX11 by the EnVision method. Meanwhile, the expression of SOX11 mRNA was also detected by reverse transcriptase-polymerase chain reaction (RT-PCR), and the association of SOX11 with such prognostic indexes as pathological typing, staging, immunophenotyping, and MIPI was analyzed using the statistical method. RESULTS: The immunohistochemistry showed that 97% of cases expressed SOX11 positive, and the RT-PCR results showed that the expression of SOX11 mRNA in the MCL patients was significantly higher than those with reactive hyperplasia lymphoid [3.097 (1.311, 6.216) and 1.058 (0.302, 2.623, respectively (p<0.05). Higher expression of SOX11 mRNA was positively correlated with some good prognostic factors such as ECOG<2, no bone marrow involvement and low-risk according to the International Prognostic Index (IPI). The comparison of the survival curves between group SOX11 mRNA

SOX11 expression as a MRD molecular marker for MCL in comparison with t(11;14) and IGH rearrangement.

The main cause of death in mantle cell lymphoma (MCL) patients is relapse due to undetermined minimal residual disease (MRD) and therefore monitoring MRD is crucial for making the best treatment decisions. The gold standard method for MRD analysis is the quantitative polymerase chain reaction. The most commonly used molecular markers for measuring MRD in MCL are: t(11;14)(q13;p32) translocation or CCND1 expression and IGH rearrangement. Such markers can, however, be found in other B cell non-Hodgkin lymphomas. Recent studies demonstrate that SOX11 expression is highly specific for MCL and could be used as a marker for measuring MRD. Moreover, evidence shows that SOX11 level could be predictive for overall survival (OS) and progression-free survival (PFS). We have measured MRD level in follow-up samples from 27 patients diagnosed with MCL using the molecular markers: t(11;14), IGH rearrangement and SOX11 expression. We compared all markers by their sensitivity, utility and quantitative range. We also examined the predictive value of SOX11 expression for OS and PFS. SOX11 expression was found to have better specificity, quantitative range and utility than the t(11;14). The predictive value of SOX11 expression was confirmed. At diagnosis, patients with high SOX11 expression had shorter PFS than patients with low SOX11 expression (p = 0.04*); differences between OS being statistically insignificant. To our best knowledge this is a first study comparing SOX11 with t(11;14) and IGH rearrangement as markers of MRD level. Moreover, in this study we confirmed that SOX11 is useful in cases when other molecular markers cannot be used.

Immunocytochemistry for SOX-11 and TFE3 as diagnostic markers for solid pseudopapillary neoplasms of the pancreas in FNA biopsies.

BACKGROUND: Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare malignant tumors that can be sampled via endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Although diagnosing SPNs can be straightforward in cases with a classic morphology and a typical immunoprofile, challenges can occur with morphologic variants or limited specimens. Recently, 2 immunohistochemical stains, SRY-related high-mobility group box 11 (SOX-11) and transcription factor E3 (TFE3), have been demonstrated to be highly sensitive and specific for SPNs in pancreatic resection specimens. The current study evaluates the diagnostic utility of these stains with EUS-FNA. METHODS: Thirteen EUS-FNA specimens from SPNs with sufficient material for immunocytochemistry were identified from 2000 to 2016. These cases were compared with 13 EUS-FNA specimens of non-SPN pancreatic neoplasms. Immunocytochemistry for SOX-11, TFE3, and ß-catenin was performed on all cell blocks and then was scored independently by 2 pathologists in a masked manner. RESULTS: Nuclear reactivity for SOX-11 was detected in 13 of 13 SPNs and in 0 of 13 non-SPNs; this resulted in sensitivity and specificity values of 100%, a positive predictive value (PPV) of 1, and a negative predictive value (NPV) of 1. Nuclear reactivity for TFE3 was detected in 9 of 13 SPNs and in 0 of 13 non-SPNs; this resulted in a sensitivity of 69.2%, a specificity of 100%, a PPV of 1, and an NPV of 0.765. Nuclear reactivity for ß-catenin was detected in 13 of 13 SPNs and in 1 of 13 non-SPNs; this resulted in a sensitivity of 100%, a specificity of 92.3%, a PPV of 0.929, and an NPV of 1. CONCLUSIONS: SOX-11 is a sensitive and specific immunocytochemical stain for SPNs in EUS-FNA specimens, and it may be useful as a diagnostic marker for distinguishing SPNs from its cytologic mimics. Cancer Cytopathol 2017;125:831-7. © 2017 American Cancer Society.

Reproducibility of SOX-11 detection in decalcified bone marrow tissue in mantle cell lymphoma patients.

Mantle cell lymphoma (MCL) usually harbors the t(11;14)(q13;q32) with overexpression of CCND1 mRNA and transcription of the cyclin D1 nuclear protein. Regardless of CCND1 status, most MCLs also express the SOX11 nuclear protein, which is thus helpful in the diagnosis of the rare CCND1-negative MCLs. Recently, SOX11 has been reported to be often negative in MCLs clinically resembling marginal zone lymphoma and recently defined as "leukemic non-nodal" MCL in the incoming revision of the WHO classification of lymphoid tumors, for which the bone marrow biopsy is commonly the first diagnostic approach. Due to the less aggressive clinical behavior of the latter MCLs, the reliable determination of the SOX11 antigen in decalcified tissue is mandatory. To this end, since little data are available in the literature, four commercially available anti-SOX11 antibodies (two polyclonal and two monoclonal) were tested on 21 positive staging bone marrow (BM) biopsies from cyclin D1/SOX11-positive MCL patients (17 fixed in B5, 4 in 10% buffered formalin) and on 9 positive BM biopsies from leukemic non-nodal MCL patients. The results were compared for specificity, sensitivity, staining strength and degree of an additional staining on myeloid precursors, also evaluating possible impact of the different fixatives used. Non-mantle cell lymphomas were also tested to address specificity. All reagents showed high sensitivity but the monoclonal code CMC38221001 provided the highest specificity and the lowest degree of non-lymphoid staining on myeloid cells. Formalin fixation generally improved the performance of most antibodies when compared to B5 fixation.

Expression of SOX11, PAX5, TTF-1 and ISL-1 in medulloblastoma.

The aim of our study was to evaluate the immunohistochemical expression of SOX11, PAX5, TTF-1 and ISL-1 in medulloblastoma (MB) to investigate their diagnostic usefulness. METHODS: Immunohistochemical expression of PAX5 (two antibodies: Dako, DAK-Pax5; and BD, clone 24), TTF-1 (Dako, 8G7G3/1), SOX11 (CL0142; Abcam) and ISL-1 (1 H9, Abcam) was analyzed using the h-score and Remmele score in 25 cases of MB. RESULTS: There were 18 MBs of classic and 7 of desmoplastic type. SOX11 was strongly expressed in all tumors. The expression of PAX5 was higher and more frequent in a case of DAK-Pax5 clone (25/25) than clone 24 (6/25). ISL-1 was positive in 11 (44%) and TTF-1 in 3 (12%) cases. ISL-1 expression correlated positively (p<0.001), while TTF-1 correlated negatively with the age of patients (p=0.039). PAX5 expression correlated with ISL-1 (p=0.039) and showed a trend toward higher expression in the desmoplastic subtype (p=0.069). CONCLUSIONS: SOX11 is strongly and robustly expressed in MBs. PAX5 expression pattern differs substantially among two antibody clones. TTF-1 and ISL-1 is associated with the age of patients.

MicroRNA-132/212 Upregulation Inhibits TGF-ß-Mediated Epithelial-Mesenchymal Transition of Prostate Cancer Cells by Targeting SOX4.

BACKGROUND: MicroRNAs (miRNAs) are noncoding RNAs that are important for embryonic stem cell development and epithelial to mesenchymal transition (EMT). Accumulating evidence indicates that miRNAs play critical roles in prostate cancer (PCa) metastasis and have potential use as therapeutic targets. Although dysregulated miR-132/212 have been suggested to be directly involved in the proliferation and invasion of multiple malignancies, the exact role of miR-132/212 in PCa has not yet been fully understood. METHODS: Real-time quantitative PCR (RT-qPCR) and bioinformatics analysis were used to validate the expression levels of miR-132/212 in PCa cell lines as well as in prostatic tissues. The biological function of miR-132/212 was evaluated by MTS, transwell, and wound healing assays, respectively. RT-qPCR and Western blot were used to study the transcript and protein expression levels. Bioinformatics tools and luciferase reporter assay were utilized to identify the molecular target of miR-132/212. Immunohistochemistry (IHC) was used to detect the expression of SOX4. RESULTS: miR-132 and miR-212 from the same gene cluster are downregulated in human PCa tissues when compared with benign prostatic hyperplasia tissues (both P < 0.05). Functionally, upregulation of miR-132/212 inhibits the migration and invasive capacity of Vcap and Lncap cells by wound-healing and transwell assays, respectively. Notably, overexpression of miR-132/212 could inhibit TGF-ß (transforming growth factor-ß)-induced EMT in Vcap and Lncap cells at both the mRNA and protein expression levels. SOX4 gene, an important EMT regulator of PCa, was identified as the target of miR-132/212 by bioinformatics tools and luciferase reporter assay. Clinically, miR-132/212 expression levels were adversely correlated with Gleason score (P < 0.001) and SOX4 expression by IHC and RT-qPCR in PCa tissues. CONCLUSION: Our data suggested that miR-132/212 may act as tumor suppressors in PCa progression through disrupting EMT process by directly targeting SOX4. Prostate 76:1560-1570, 2016. © 2016 Wiley Periodicals, Inc.

In situ carcinoma developed over oral lichen planus: a case report with analysis of BUB3, p16, p53, Ki67 and SOX4 expression.

Oral lichen planus (OLP) represents a common mucocutaneous disease. Various authors have suggested that OLP has malignant potential; however, the mechanisms involved in malignant transformation have not yet been elucidated. A 79-year-old man presented a white lesion for five months in the buccal mucosa diagnosed as OLP. After two months using 0.05% clobetasol ointment for treatment, the lesion became ulcerated. A new biopsy of the same lesion was performed, and histological analysis showed an in situ oral carcinoma (ISOC). An immunohistochemistry panel was performed, and p16 expression was negative in OLP, however, it showed weak cytoplasmic staining in ISOC. There was strong nuclear BUB3 staining in both OLP and ISOC areas. p53 showed less intense nuclear staining in both regions. Ki67 was negative in OLP area, but showed nuclear staining in the ISOC. SOX4 was negative in both studied areas. BUB3 expression, first reported in this case, and the p16 expression may suggest some influence of these genes on pathogenesis or malignant potential of OLP.

In situ carcinoma developed over oral lichen planus: a case report with analysis of BUB3, p16, p53, Ki67 and SOX4 expression

AbstractOral lichen planus (OLP) represents a common mucocutaneous disease. Various authors have suggested that OLP has malignant potential; however, the mechanisms involved in malignant transformation have not yet been elucidated. A 79-year-old man presented a white lesion for five months in the buccal mucosa diagnosed as OLP. After two months using 0.05% clobetasol ointment for treatment, the lesion became ulcerated. A new biopsy of the same lesion was performed, and histological analysis showed an in situ oral carcinoma (ISOC). An immunohistochemistry panel was performed, and p16 expression was negative in OLP, however, it showed weak cytoplasmic staining in ISOC. There was strong nuclear BUB3 staining in both OLP and ISOC areas. p53 showed less intense nuclear staining in both regions. Ki67 was negative in OLP area, but showed nuclear staining in the ISOC. SOX4 was negative in both studied areas. BUB3 expression, first reported in this case, and the p16 expression may suggest some influence of these genes on pathogenesis or malignant potential of OLP.

SOX4 is overexpressed in diffusely infiltrating astrocytoma and confers poor prognosis.

The SOX4 (sex-determining region Y-related high-mobility-group box transcription factor 4) gene plays critical roles in embryonic development and cell-fate determination. Recently, SOX4 overexpression has been found in various tumors. However, its expression status and prognostic significance in astrocytoma remain unknown. In this study, SOX4 expression in diffusely infiltrating astrocytoma (WHO grades II-IV) tissues (in comparison with pilocytic astrocytomas) was examined by immunohistochemistry, and its relevance with prognosis was analyzed. Our data showed that SOX4 was over-expressed in diffusely infiltrating astrocytomas and its expression was positively correlated with astrocytoma grade (WHO grades II-IV). Significantly, Kaplan-Meier analysis revealed that SOX4 nuclear overexpression (SOX4-N) was associated with poorer progression-free survival (PFS) and disease-specific survival (DSS) in diffusely infiltrating astrocytoma patients (P < 0.05). Cox regression analysis further showed that nuclear SOX4-N was a significant independent negative prognostic factor for these patients.

Sox11 promotes endogenous neurogenesis and locomotor recovery in mice spinal cord injury.

We introduced a lentiviral vector containing the Sox11 gene into injured spinal cords of mice to evaluate the therapeutic potential of Sox11 in spinal cord injury. Sox11 markedly improved locomotor recovery after spinal cord injury and this recovery was accompanied by an up-regulation of Nestin/Doublecortin expression in the injured spinal cord. Sox11 was mainly located in endogenous neural stem cells lining the central canal and in newly-generated neurons in the spinal cord. In addition, Sox 11 significantly induced expressions of BDNF in the spinal cords of LV-Sox11-treated mice. We concluded that Sox11 induced activation of endogenous neural stem cells into neuronal determination and migration within the injured spinal cord. The resultant increase of BDNF at the injured site might form a distinct neurogenic niche which induces a final neuronal differentiation of these neural stem cells. Enhancing Sox11 expression to induce neurogenic differentiation of endogenous neural stem cells after injury may be a promising strategy in restorative therapy after SCI in mammals.

Assessment of SOX11 expression in routine lymphoma tissue sections: characterization of new monoclonal antibodies for diagnosis of mantle cell lymphoma.

The diagnosis of mantle cell lymphoma (MCL) can be difficult, especially when no t(11;14) translocation and cyclin D1 overexpression can be detected. In such cases, the transcription factor SOX11 represents an important diagnostic marker, as it is expressed in most MCLs and, in particular, in all cyclin D1-negative MCLs reported so far. A reliable anti-SOX11 antibody is therefore a very useful tool for routine diagnosis. Here, we characterize the new monoclonal anti-SOX11 antibodies, suitable for Western blot assay and immunohistochemistry (IHC) on formalin-fixed paraffin-embedded tissue; we tested them on a large series of primary lymphoid tumors and compared these results with those of other routinely used antibodies. Moreover, we show that IHC results depend on transcription levels of SOX11, which suggests that posttranscriptional and posttranslational modifications do not significantly affect cutoff levels for IHC detection of SOX11.

Polyclonal antibody targeting SOX11 cannot differentiate mantle cell lymphoma from B-cell non-Hodgkin lymphomas.

OBJECTIVES: To determine whether SOX11 is a diagnostic marker of mantle cell lymphoma (MCL). METHODS: We analyzed SOX11 expression in 349 B-cell non-Hodgkin lymphomas (B-NHLs) via immunohistochemistry. RESULTS: Nuclear staining of SOX11 was observed in 54 (93.1%) of 58 MCLs. We noticed that SOX11 protein was also expressed on the nuclei in 8 (21.6%) of 37 B-lymphoblastic lymphomas, 45 (32.6%) of 138 diffuse large B-cell lymphomas, 15 (44.1%) of 34 follicular lymphomas, 8 (30.8%) of 26 Burkitt lymphomas, 2 (10.0%) of 20 chronic lymphocytic leukemia/small cell lymphomas, and 3 (18.8%) of 16 marginal zone lymphomas. CONCLUSIONS: Although the positive rate of SOX11 expression in MCL was significantly higher than other B-NHLs (P < .001), polyclonal antibody targeting SOX11 is not able to identify MCL from B-NHLs because the nuclear staining of SOX11 was widely positive in B-NHLs.

The role of SOX11 in mantle cell lymphoma.

The mechanism of SOX11 function has been widely published recently mainly focused on histone modifications. Besides diagnostic value in mantle cell lymphoma (MCL), SOX11 has also prognostic significance. Although it can also be observed in a fraction of other T and B-cell lymphomas, a monoclonal antibody, called SOX11-C1, may improve the function of SOX11 in both diagnosis and prognosis evaluation. In addition, detection of modified SOX11 cDNA by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) has a higher sensitivity than traditional CCND1 examination in minimal residual disease (MRD) detection, which is an appealing option for predicting disease outcome and status.