Deregulated expression of p16INK4a and p53 pathway members in benign and malignant myoepithelial tumours of the salivary glands.

Aims: Myoepithelial salivary gland tumours are uncommon and follow an unpredictable biological course. The aim was to examine their molecular background to acquire a better understanding of their clinical behaviour.

Methods And Results: Expression of protein (E2F1, p16(INK4a), p53, cyclin D1, Ki67 and Polycomb group proteins BMI-1, MEL-18 and EZH2) was investigated in 49 benign and 30 primary malignant myoepithelial tumours and five histologically benign recurrences by immunohistochemistry and the findings correlated with histopathological characteristics.

High expression of Polycomb group protein EZH2 predicts poor survival in salivary gland adenoid cystic carcinoma.

Background: The prognosis of adenoid cystic carcinoma (ACC), a malignant salivary gland tumour, depends on clinicopathological parameters. To decipher the biological behaviour of ACC, and to identify patients at risk of developing metastases, additional markers are needed.

Methods: Expression of the cell cycle proteins p53, cyclin D1, p16(INK4a), E2F1 and Ki-67, together with the Polycomb group (PcG) proteins BMI-1, MEL-18, EZH2 and EED was investigated immunohistochemically 21 formalin-fixed, paraffin-embedded primary ACCs in relation to tumour characteristics.

Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features.

Objectives: Polycomb group (PcG) proteins are involved in maintenance of cell identity and proliferation. The protein EZH2 is overexpressed in disseminated prostate cancer, implicating a role of PcG complexes in tumor progression. In this study, we evaluated the expression of eight members of both PcG complexes in clinicopathologically defined prostate cancer.

Expression of the polycomb-group gene BMI1 is related to an unfavourable prognosis in primary nodal DLBCL.

Background: Clinical outcome in patients with diffuse large B cell lymphomas (DLBCL) is highly variable and poorly predictable. Microarray studies showed that patients with DLBCL with a germinal centre B cell-like (GCB) phenotype have a better prognosis than those with an activated B cell-like (ABC) phenotype. The BMI1 proto-oncogene was identified as one of the genes present in the signature of the ABC type of DLBCL, associated with a poor prognosis.

Of mice, flies, and man: the emerging role of polycomb-group genes in human malignant lymphomas.

Genes belonging to the Polycomb group (PcG) are responsible for the maintenance of cell identity and are directly involved in epigenetic gene silencing. They perform a vital role in the regulation of embryogenesis but also contribute to various adult processes, including regulation of the cell cycle and lymphopoiesis. Experimental model systems have demonstrated that enhanced expression of individual PcG genes, such as Bmi1, results in the development of B-cell and T-cell lymphomas.

Expression of the p16(INK4a) gene product, methylation of the p16(INK4a) promoter region and expression of the polycomb-group gene BMI-1 in squamous cell lung carcinoma and premalignant endobronchial lesions.

It is generally assumed that squamous cell carcinoma develops in a stepwise manner from normal bronchial epithelium towards cancer by the accumulation of (epi)genetic alterations. Several mechanisms including mutations and homozygous deletions or hypermethylation of the p16(INK4a) promoter region can cause loss of p16 expression. Recent studies suggest overexpression of the polycomb-group gene BMI-1 might also down-regulate p16 expression.

Deregulated expression of Polycomb-group oncogenes in human malignant lymphomas and epithelial tumors.

Genes belonging to the Polycomb-group (PcG) are epigenetic gene silencers with a vital role in the maintenance of cell identity. They contribute to regulation of various processes in both embryos and adults, including the cell cycle and lymphopoiesis. A growing body of work has linked human PcG genes to various hematological and epithelial cancers, identifying novel mechanisms of malignant transformation and paving the way to development of new cancer treatments and identification of novel diagnostic markers.

Increased expression of the EZH2 polycomb group gene in BMI-1-positive neoplastic cells during bronchial carcinogenesis.

Polycomb group (PcG) genes are responsible for maintenance of cellular identity and contribute to regulation of the cell cycle. Recent studies have identified several PcG genes as oncogenes, and a role for PcG proteins in human oncogenesis is suspected. We investigated the expression of BMI-1 and EZH2 PcG oncogenes in human bronchial squamous cell carcinomas (SCCs) and bronchial premalignant precursor lesions (PLs).

Distinct expression patterns of polycomb oncoproteins and their binding partners during the germinal center reaction.

Polycomb group (PcG) genes encode two chromatin-binding protein complexes, the PRC1 and the PRC2 PcG complexes, which are essential for the maintenance of cell identity and play a role in oncogenesis. PcG complexes were recently identified as novel regulators of hematopoiesis, and appear to be expressed in a non-overlapping pattern in resting and mature follicular B cells. Using highly specific antisera in combination with immunohistochemistry and triple immunofluorescence, we investigated the expression pattern of nine human PcG genes in germinal center (GC) B cells and highly purified germinal center B cell subpopulations.

Unique polycomb gene expression pattern in Hodgkin's lymphoma and Hodgkin's lymphoma-derived cell lines.

Human Polycomb-group (PcG) genes play a crucial role in the regulation of embryonic development and regulation of the cell cycle and hematopoiesis. PcG genes encode proteins that form two distinct PcG complexes, involved in maintenance of cell identity and gene silencing patterns. We recently showed that expression of the BMI-1 and EZH2 PcG genes is separated during normal B-cell development in germinal centers, whereas Hodgkin/Reed-Sternberg (H/RS) cells co-express BMI-1 and EZH2.

Poorly differentiated breast carcinoma is associated with increased expression of the human polycomb group EZH2 gene.

Polycomb group (PcG) genes contribute to the maintenance of cell identity, cell cycle regulation, and oncogenesis. We describe the expression of five PcG genes (BMI-1, RING1, HPC1, HPC2, and EZH2) innormal breast tissues, invasive breast carcinomas, and their precursors. Members of the HPC-HPH/PRC1 PcG complex, including BMI-1, RING1, HPC1, and HPC2, were detected in normal resting and cycling breast cells.

Site-specific expression of polycomb-group genes encoding the HPC-HPH/PRC1 complex in clinically defined primary nodal and cutaneous large B-cell lymphomas.

Polycomb-group (PcG) genes preserve cell identity by gene silencing, and contribute to regulation of lymphopoiesis and malignant transformation. We show that primary nodal large B-cell lymphomas (LBCLs), and secondary cutaneous deposits from such lymphomas, abnormally express the BMI-1, RING1, and HPH1 PcG genes in cycling neoplastic cells. By contrast, tumor cells in primary cutaneous LBCLs lacked BMI-1 expression, whereas RING1 was variably detected.

Self-renewal of hematopoietic and leukemic stem cells: a central role for the Polycomb-group gene Bmi-1.

Self-renewal of hematopoietic stem cells is vital for the sustained daily production of blood cells. Two recent studies have shown that the Polycomb-group gene Bmi-1 is indispensable for regulation of self-renewal by normal and leukemic stem cells. This identifies Polycomb-group genes as potential targets for therapeutic intervention in leukemia, and possibly other forms of cancer.

Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus.

A comprehensive analysis of 53 penile carcinomas was performed to determine which mechanisms might be involved in the disruption of the p16(INK4A)/cyclin D/Rb pathway. To that end, human papillomavirus (HPV) presence, p16(INK4A) expression and promoter methylation, and expression of the BMI-1 polycomb gene product were studied. Sixteen (30%) of the carcinomas were found to harbour high-risk HPV DNA, 15 of which contained HPV 16.

TCRBV CDR3 diversity of CD4+ and CD8+ T-lymphocytes in HIV-infected individuals.

TCRBV CDR3 repertoire diversity was analyzed in a cross-sectional study of HIV-infected individuals by CDR3 fingerprinting/spectratyping and single strand conformation polymorphism (SSCP). Most TCRBV families were detected in CD4+ cells of HIV-infected patients with CD4 counts ranging from 35 to 1103. In patients with CD4 counts >500, CD4+ TCRBV CDR3 fingerprinting profiles contained subtle variations with generally gaussian-distributed sizes.

Polycomb-group genes as regulators of mammalian lymphopoiesis.

Polycomb proteins form DNA-binding protein complexes with gene-suppressing activity. They maintain cell identity but, also, contribute to the regulation of cell proliferation. Mice with mutated Polycomb-group genes exhibit various hematological disorders, ranging from the loss of mature B and T cells to development of lymphomas.

Differential expression of human Polycomb group proteins in various tissues and cell types.

Polycomb group proteins are involved in the maintenance of cellular identity. As multimeric complexes they repress cell type-specific sets of target genes. One model predicts that the composition of Polycomb group complexes determines the specificity for their target genes.

T cell expansions in lymph nodes and peripheral blood in HIV-1-infected individuals: effect of antiretroviral therapy.

Objective: To evaluate dynamics in CD8 T cell expansions during highly active antiretroviral therapy (HAART).

Design: Various T cell subsets were isolated from blood and lymph nodes and analysed for T cell receptor (TCR) diversity.

Methods: TCR complementarity determining region 3 (CDR3) spectratyping and single-strand conformation polymorphism (SSCP) analyses were performed in combination with sequencing to assess clonality of the subsets.

Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma.

Polycomb-group (PcG) proteins, such as BMI-1 and EZH2, form multimeric gene-repressing complexes involved in axial patterning, hematopoiesis, and cell cycle regulation. In addition, BMI-1 is involved in experimental lymphomagenesis. Little is known about its role in human lymphomagenesis.

Distinct BMI-1 and EZH2 expression patterns in thymocytes and mature T cells suggest a role for Polycomb genes in human T cell differentiation.

BMI-1 and EZH2 Polycomb-group (PcG) proteins belong to two distinct protein complexes involved in the regulation of hematopoiesis. Using unique PcG-specific antisera and triple immunofluorescence, we found that mature resting peripheral T cells expressed BMI-1, whereas dividing blasts were EZH2(+). By contrast, subcapsular immature double-negative (DN) (CD4(-)/CD8(-)) T cells in the thymus coexpressed BMI-1 and EZH2 or were BMI-1 single positive.

Ig heavy chain CDR3 size diversities are similar after conventional peripheral blood and ex vivo expanded hematopoietic cell transplants.

It is largely unknown whether the immune repertoire can be reconstituted successfully after high-dose chemotherapy and transplantation using ex vivo expanded hematopoietic stem cell (HSC) grafts. It is critically important for the transplant outcome that immune repertoire reconstitution progresses after ex vivo expanded HSC graft transplants at least as efficiently as that seen after conventional HSC transplants. Previously, we showed that the T cell receptor V beta (TCRVB) third complementarity determining region (CDR3) diversification after ex vivo expanded bone marrow (BM) HSC graft transplants was similar to that seen after conventional peripheral blood stem cell transplants (PBSCTs).

The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma.

Polycomb group (PcG) proteins are involved in the stable transmittance of the repressive state of their gene targets throughout the cell cycle. Mis-expression of PcG proteins can lead to proliferative defects and tumorigenesis. There are two separate multimeric PcG protein complexes: an EED-EZH2-containing complex and a BMI1-RING1-containing complex.

Ex vivo-expanded hematopoietic cell graft recipients exhibit T cell repertoire diversity similar to that seen after conventional stem cell transplants.

The feasibility of using ex vivo-expanded hematopoietic progenitor cells to reconstitute hematopoiesis after high-dose chemotherapy is presently being examined. Early studies have shown that myeloid and erythroid hematopoiesis can be successfully reconstituted after high-dose chemotherapy and ex vivo-expanded hematopoietic cell transplantation. The lymphoid reconstitution, however, has not been addressed previously.

Coexpression of BMI-1 and EZH2 polycomb group genes in Reed-Sternberg cells of Hodgkin's disease.

The human BMI-1 and EZH2 polycomb group (PcG) proteins are constituents of two distinct complexes of PcG proteins with gene regulatory activity. PcG proteins ensure correct embryonic development by suppressing homeobox genes, and they also contribute to regulation of lymphopoiesis. The two PcG complexes are thought to regulate different target genes and probably have different tissue distributions.