26 results on '"Emely Möller"'
Search Results
2. Reciprocal modulation of mesenchymal stem cells and tumor cells promotes lung cancer metastasis
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Giulia Fregni, Mathieu Quinodoz, Emely Möller, Joanna Vuille, Sabine Galland, Carlo Fusco, Patricia Martin, Igor Letovanec, Paolo Provero, Carlo Rivolta, Nicolo Riggi, and Ivan Stamenkovic
- Subjects
Medicine ,Medicine (General) ,R5-920 - Abstract
Metastasis is a multi-step process in which direct crosstalk between cancer cells and their microenvironment plays a key role. Here, we assessed the effect of paired tumor-associated and normal lung tissue mesenchymal stem cells (MSCs) on the growth and dissemination of primary human lung carcinoma cells isolated from the same patients. We show that the tumor microenvironment modulates MSC gene expression and identify a four-gene MSC signature that is functionally implicated in promoting metastasis. We also demonstrate that tumor-associated MSCs induce the expression of genes associated with an aggressive phenotype in primary lung cancer cells and selectively promote their dissemination rather than local growth. Our observations provide insight into mechanisms by which the stroma promotes lung cancer metastasis. Keywords: Tumor-associated MSCs, lung cancer, metastasis, GREM1, LOXL2, ADAMTS12, ITGA11
- Published
- 2018
- Full Text
- View/download PDF
3. Supplementary Data from FUS-CREB3L2/L1–Positive Sarcomas Show a Specific Gene Expression Profile with Upregulation of CD24 and FOXL1
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Fredrik Mertens, Henryk A. Domanski, Srinivas Veerla, Linda Magnusson, Jason L. Hornick, and Emely Möller
- Abstract
Supplementary Figures S1-S4; Supplementary Tables S1-S2.
- Published
- 2023
4. Data from FUS-CREB3L2/L1–Positive Sarcomas Show a Specific Gene Expression Profile with Upregulation of CD24 and FOXL1
- Author
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Fredrik Mertens, Henryk A. Domanski, Srinivas Veerla, Linda Magnusson, Jason L. Hornick, and Emely Möller
- Abstract
Purpose: Low-grade fibromyxoid sarcoma (LGFMS) is typically characterized by the specific translocation t(7;16)(q33;p11) and the corresponding fusion gene FUS-CREB3L2. The present study aimed to extract LGFMS-specific, and putatively FUS-CREB3L2–dependent, gene expression patterns to learn more about the pathogenesis of this tumor.Experimental Design: We carried out single nucleotide polymorphism (SNP) and global gene expression array analyses, and/or immunohistochemical (IHC) analyses on 24 LGFMS tumor biopsies. Tumor types that are important differential diagnoses to LGFMS were included as comparison in the gene and protein expression analyses. In addition, cells that stably expressed FUS-CREB3L2 were analyzed with gene expression array and the influence of FUS-CREB3L2 on gene expression was investigated in vitro.Results: The SNP array analysis detected recurrent microdeletions in association with the t(7;16) chromosomal breakpoints and gain of 7q in cases with ring chromosomes. Gene expression analysis clearly distinguished LGFMS from morphologically similar tumors and MUC4 was identified as a potential diagnostic marker for LGFMS by gene expression and IHC analysis. FOXL1 was identified as the top upregulated gene in LGFMS and CD24 was upregulated in both LGFMS tumors and FUS-CREB3L2 expressing cells. FUS-CREB3L2 was capable of activating transcription from CD24 regulatory sequences in luciferase assays, suggesting an important role for the upregulation of this gene in LGFMS.Conclusions: The gene expression profile of LGFMS is distinct from that of soft tissue tumors with similar morphology. The data could be used to identify a potential diagnostic marker for LGFMS and to identify possible FUS-CREB3L2 regulated genes. Clin Cancer Res; 17(9); 2646–56. ©2011 AACR.
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- 2023
5. EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma
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Emely Möller, Viviane Praz, Sanalkumar Rajendran, Rui Dong, Alexandra Cauderay, Yu-Hang Xing, Lukuo Lee, Carlo Fusco, Liliane C. Broye, Luisa Cironi, Sowmya Iyer, Shruthi Rengarajan, Mary E. Awad, Beverly Naigles, Igor Letovanec, Nicola Ormas, Giovanna Finzi, Stefano La Rosa, Fausto Sessa, Ivan Chebib, G. Petur Nielsen, Antonia Digklia, Dimitrios Spentzos, Gregory M. Cote, Edwin Choy, Martin Aryee, Ivan Stamenkovic, Gaylor Boulay, Miguel N. Rivera, and Nicolò Riggi
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Oncogene Proteins ,Multidisciplinary ,Oncogene Proteins, Fusion ,Carcinogenesis ,General Physics and Astronomy ,Sarcoma ,Soft Tissue Neoplasms ,General Chemistry ,Oncogenes ,General Biochemistry, Genetics and Molecular Biology ,Chromatin ,Clear Cell ,Carcinogenesis/genetics ,Chromatin/genetics ,Humans ,Oncogene Proteins, Fusion/genetics ,Oncogene Proteins, Fusion/metabolism ,RNA-Binding Protein EWS/genetics ,Sarcoma, Clear Cell/genetics ,Sarcoma, Clear Cell/pathology ,Soft Tissue Neoplasms/genetics ,RNA-Binding Protein EWS ,Sarcoma, Clear Cell ,Fusion - Abstract
Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.
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- 2021
6. Reciprocal modulation of mesenchymal stem cells and tumor cells promotes lung cancer metastasis
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Joanna Vuille, Nicolo Riggi, Emely Möller, Paolo Provero, Mathieu Quinodoz, Sabine Galland, Patricia Martin, Giulia Fregni, Igor Letovanec, Carlo Rivolta, Carlo Fusco, and Ivan Stamenkovic
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Male ,0301 basic medicine ,Lung Neoplasms ,ITGA11 ,lcsh:Medicine ,Cell Communication ,Metastasis ,Mice ,Tumor Microenvironment ,Tumor-associated MSCs ,Neoplasm Metastasis ,Aged, 80 and over ,lcsh:R5-920 ,GREM1 ,General Medicine ,Middle Aged ,ADAMTS12 ,LOXL2 ,Gene Expression Regulation, Neoplastic ,Female ,lcsh:Medicine (General) ,Research Paper ,Cell signaling ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Stroma ,medicine ,Carcinoma ,metastasis ,Animals ,Humans ,Lung cancer ,Aged ,Biomarkers ,Disease Models, Animal ,Gene Expression Profiling ,Lung Neoplasms/genetics ,Lung Neoplasms/metabolism ,Lung Neoplasms/pathology ,Mesenchymal Stromal Cells/metabolism ,Neoplasm Grading ,Neoplasm Staging ,Transcriptome ,Tumor Microenvironment/genetics ,Xenograft Model Antitumor Assays ,lung cancer ,Tumor microenvironment ,lcsh:R ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,medicine.disease ,030104 developmental biology ,Cancer cell ,Cancer research - Abstract
Metastasis is a multi-step process in which direct crosstalk between cancer cells and their microenvironment plays a key role. Here, we assessed the effect of paired tumor-associated and normal lung tissue mesenchymal stem cells (MSCs) on the growth and dissemination of primary human lung carcinoma cells isolated from the same patients. We show that the tumor microenvironment modulates MSC gene expression and identify a four-gene MSC signature that is functionally implicated in promoting metastasis. We also demonstrate that tumor-associated MSCs induce the expression of genes associated with an aggressive phenotype in primary lung cancer cells and selectively promote their dissemination rather than local growth. Our observations provide insight into mechanisms by which the stroma promotes lung cancer metastasis., Highlights • Distinct gene expression profiles distinguish normal lung and tumor-associated MSCs. • MSCs induce EMT- and hypoxia-related genes in primary tumor cells and promote their metastatic potential. • A 4-gene T-MSC signature is involved in MSC-induced metastasis promotion. The tumor microenvironment, which includes mesenchymal stem cells (MSCs) among many other stromal cell types, plays a fundamental role in cancer metastasis. Although MSCs are suggested to participate in tumor progression, most studies thus far have been performed on bone marrow-derived MSCs and cancer cell lines. Using primary human pulmonary MSCs and paired lung cancer cells, we show that tumor cells modulate MSCs to acquire properties, including a four-gene signature, which allow them to promote tumor dissemination. Our results provide insight into the mutual cancer cell-stromal cell modulation that drives tumor dissemination.
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- 2018
- Full Text
- View/download PDF
7. Recurrent Rearrangement of the PHF1 Gene in Ossifying Fibromyxoid Tumors
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Raf Sciot, Emely Möller, Karolin Hansén Nord, Jenny Nilsson, Linda Magnusson, Fredrik Mertens, Samuel Gebre-Medhin, Olle Larsson, Nils Mandahl, Maria Debiec-Rychter, Otte Brosjö, Fredrik Vult von Steyern, Henryk A. Domanski, Vickie Y. Jo, and Christopher D.M. Fletcher
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Molecular Sequence Data ,Polycomb-Group Proteins ,Bone Neoplasms ,Locus (genetics) ,Biology ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Pathology and Forensic Medicine ,Fusion gene ,Rapid amplification of cDNA ends ,Recurrence ,medicine ,Chromosomes, Human ,Humans ,Cell Shape ,In Situ Hybridization, Fluorescence ,Metaphase ,Aged ,Aged, 80 and over ,Gene Rearrangement ,Paraffin Embedding ,Base Sequence ,medicine.diagnostic_test ,Breakpoint ,Chromosome Breakage ,Middle Aged ,medicine.disease ,DNA-Binding Proteins ,Fusion transcript ,Cytogenetic Analysis ,Fibroma, Ossifying ,Female ,Chromosome breakage ,Fibroma ,Transcription Factors ,Fluorescence in situ hybridization - Abstract
Ossifying fibromyxoid tumor (OFMT) is a soft tissue tumor of unknown lineage. Although most cases are histologically and clinically benign, some show malignant morphological features and local recurrences are not uncommon; a few may even metastasize. In the present study, cytogenetic analysis identified different structural rearrangements of chromosome band 6p21 in tumor cells from three cases of OFMT, including one with typical, one with atypical, and one with malignant morphological features. Mapping of the 6p21 breakpoint by fluorescence in situ hybridization (FISH) indicated that the PHF1 gene was rearranged in all three cases. Further FISH, 5'-rapid amplification of cDNA ends, and RT-PCR analyses disclosed an EP400/PHF1 fusion transcript in one of the cases. Interphase FISH on tumor sections from 13 additional cases of OFMT showed rearrangement of the PHF1 locus in four of four typical, two of three atypical, and one of six malignant lesions. Thus, the PHF1 gene, previously shown to be the 3'-partner of fusion genes in endometrial stromal tumors, is also recurrently involved in the pathogenesis of OFMTs, irrespective of whether they are diagnosed as typical, atypical, or malignant lesions. The PHF1 protein interacts with the polycomb-repressive complex 2 (PRC2), which, in turn, regulates the expression of a variety of developmental genes. Thus, the results indicate that deregulation of PRC2 target genes is crucial for OFMT development.
- Published
- 2012
8. FOSL1 as a candidate target gene for 11q12 rearrangements in desmoplastic fibroblastoma
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Maria Debiec-Rychter, Clelia Tiziana Storlazzi, Emely Möller, Raf Sciot, Domenico Trombetta, Fredrik Mertens, Karolin Hansén Nord, and Gemma Macchia
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Adult ,Male ,Adenomatous polyposis coli ,Adenomatous Polyposis Coli Protein ,Chromosomal translocation ,Locus (genetics) ,Translocation, Genetic ,Pathology and Forensic Medicine ,Diagnosis, Differential ,Neoplasms, Muscle Tissue ,medicine ,Humans ,Gardner Syndrome ,Molecular Biology ,beta Catenin ,Aged ,Oligonucleotide Array Sequence Analysis ,Genetics ,biology ,medicine.diagnostic_test ,Chromosomes, Human, Pair 11 ,Gene Expression Profiling ,Chromosome Breakage ,Karyotype ,Cell Biology ,Middle Aged ,FOSL1 ,Gene expression profiling ,Cytogenetic Analysis ,biology.protein ,Chromosomes, Human, Pair 5 ,Female ,Chromosome breakage ,Proto-Oncogene Proteins c-fos ,Fluorescence in situ hybridization - Abstract
Desmoplastic fibroblastoma (DF) is a benign fibroblastic/myofibroblastic tumor. Cytogenetic analyses have revealed consistent rearrangement of chromosome band 11q12, strongly suggesting that this region harbors a gene of pathogenetic importance. To identify the target gene of the 11q12 rearrangements, we analyzed six cases diagnosed as DF using chromosome banding, fluorescence in situ hybridization (FISH), single-nucleotide polymorphism array and gene expression approaches. Different structural rearrangements involving 11q12 were found in five of the six cases. Metaphase FISH analyses in two of them mapped the 11q12 breakpoints to an ∼20-kb region, harboring FOSL1. Global gene expression profiling followed by quantitative real-time PCR showed that FOSL1 was expressed at higher levels in DF with 11q12 rearrangements than in desmoid-type fibromatoses. Furthermore, FOSL1 was not upregulated in the single case of DF that did not show cytogenetic involvement of 11q12; instead this tumor was found to display a hemizygous loss on 5q, including the APC (adenomatous polyposis coli) locus, raising the possibility that it actually was a misdiagnosed Gardner fibroma. 5'RACE-PCR in two 11q12-positive DF did not identify any fusion transcripts. Thus, in agreement with the finding at chromosome banding analysis that varying translocation partners are involved in the 11q12 rearrangement, the molecular data suggest that the functional outcome of the 11q12 rearrangements is deregulated expression of FOSL1.Laboratory Investigation advance online publication, 12 March 2012; doi:10.1038/labinvest.2012.46. ispartof: Laboratory Investigation vol:92 issue:5 pages:735-743 ispartof: location:United States status: published
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- 2012
9. MUC4 Is a Highly Sensitive and Specific Marker for Low-grade Fibromyxoid Sarcoma
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Fredrik Mertens, Paola Dal Cin, Jason L. Hornick, Christopher D.M. Fletcher, Emely Möller, and Leona A. Doyle
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Solitary fibrous tumor ,Adolescent ,Fibrosarcoma ,Gene Expression ,Soft Tissue Neoplasms ,Biology ,Cell morphology ,Sensitivity and Specificity ,Pathology and Forensic Medicine ,Low-grade fibromyxoid sarcoma ,Young Adult ,Biomarkers, Tumor ,Dermatofibrosarcoma protuberans ,medicine ,Humans ,Child ,Aged ,Aged, 80 and over ,Mucin-4 ,medicine.diagnostic_test ,Gene Expression Profiling ,Fibroblastic Neoplasm ,Gene rearrangement ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Up-Regulation ,Child, Preschool ,Surgery ,Sarcoma ,Anatomy ,Fluorescence in situ hybridization - Abstract
Low-grade fibromyxoid sarcoma (LGFMS) is a distinctive fibroblastic neoplasm that is characterized by alternating collagenous and myxoid areas, deceptively bland spindle cell morphology, a whorling architecture, and a t(7;16) translocation involving FUS and CREB3L2. Owing to variable morphology and a lack of discriminatory markers, LGFMS can be difficult to distinguish from benign mesenchymal tumors and other low-grade sarcomas. Gene expression profiling has identified differential upregulation of the mucin 4 (MUC4) gene in LGFMS compared with histologically similar tumors. MUC4 is a transmembrane glycoprotein that functions in cell growth signaling pathways; aberrant MUC4 expression has been reported in various carcinomas. We investigated MUC4 protein expression by immunohistochemistry in LGFMS and in other soft tissue tumors to determine the potential diagnostic use of this novel marker. Whole-tissue sections of 309 tumors were evaluated: 49 LGFMSs (all with FUS gene rearrangement confirmed by fluorescence in situ hybridization), 40 soft tissue perineuriomas, 40 myxofibrosarcomas, 20 cellular myxomas, 20 solitary fibrous tumors, 20 low-grade malignant peripheral nerve sheath tumors, 20 cases of desmoid fibromatosis, 20 neurofibromas, 20 schwannomas, 20 monophasic synovial sarcomas, 20 cases of dermatofibrosarcoma protuberans, 10 myxoid liposarcomas, and 10 extraskeletal myxoid chondrosarcomas. The LGFMS cases included 7 with marked hypercellularity, 4 with prominent hemangiopericytoma-like vessels, 3 with giant collagen rosettes, 3 with epithelioid morphology, 2 with focal nuclear pleomorphism, and 2 with areas of sclerosing epithelioid fibrosarcoma. All 49 LGFMS cases (100%) showed cytoplasmic staining for MUC4, which was usually diffuse and intense. All the other tumor types were negative for MUC4, apart from 6 (30%) monophasic synovial sarcomas. In conclusion, MUC4 is a highly sensitive and quite specific immunohistochemical marker for LGFMS, and can be helpful to distinguish this tumor type from histologic mimics.
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- 2011
10. FUS-CREB3L2/L1–Positive Sarcomas Show a Specific Gene Expression Profile with Upregulation of CD24 and FOXL1
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Emely Möller, Jason L. Hornick, Henryk A. Domanski, Srinivas Veerla, Fredrik Mertens, and Linda Magnusson
- Subjects
Adult ,Male ,Cancer Research ,Adolescent ,Oncogene Proteins, Fusion ,Fibrosarcoma ,Nerve Tissue Proteins ,Soft Tissue Neoplasms ,Single-nucleotide polymorphism ,Biology ,Fusion gene ,Young Adult ,Gene expression ,Humans ,Cyclic AMP Response Element-Binding Protein ,Gene ,Aged ,Oligonucleotide Array Sequence Analysis ,CD24 ,Gene Expression Profiling ,CD24 Antigen ,Forkhead Transcription Factors ,Sarcoma ,Middle Aged ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,Basic-Leucine Zipper Transcription Factors ,Oncology ,Regulatory sequence ,Cancer research ,RNA-Binding Protein FUS ,Female - Abstract
Purpose: Low-grade fibromyxoid sarcoma (LGFMS) is typically characterized by the specific translocation t(7;16)(q33;p11) and the corresponding fusion gene FUS-CREB3L2. The present study aimed to extract LGFMS-specific, and putatively FUS-CREB3L2–dependent, gene expression patterns to learn more about the pathogenesis of this tumor. Experimental Design: We carried out single nucleotide polymorphism (SNP) and global gene expression array analyses, and/or immunohistochemical (IHC) analyses on 24 LGFMS tumor biopsies. Tumor types that are important differential diagnoses to LGFMS were included as comparison in the gene and protein expression analyses. In addition, cells that stably expressed FUS-CREB3L2 were analyzed with gene expression array and the influence of FUS-CREB3L2 on gene expression was investigated in vitro. Results: The SNP array analysis detected recurrent microdeletions in association with the t(7;16) chromosomal breakpoints and gain of 7q in cases with ring chromosomes. Gene expression analysis clearly distinguished LGFMS from morphologically similar tumors and MUC4 was identified as a potential diagnostic marker for LGFMS by gene expression and IHC analysis. FOXL1 was identified as the top upregulated gene in LGFMS and CD24 was upregulated in both LGFMS tumors and FUS-CREB3L2 expressing cells. FUS-CREB3L2 was capable of activating transcription from CD24 regulatory sequences in luciferase assays, suggesting an important role for the upregulation of this gene in LGFMS. Conclusions: The gene expression profile of LGFMS is distinct from that of soft tissue tumors with similar morphology. The data could be used to identify a potential diagnostic marker for LGFMS and to identify possible FUS-CREB3L2 regulated genes. Clin Cancer Res; 17(9); 2646–56. ©2011 AACR.
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- 2011
11. Autopsy
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Fredrik Mertens, Jason L. Hornick, Leona A. Doyle, and Emely Möller
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Pathology ,medicine.medical_specialty ,Chemistry ,medicine ,Cell Biology ,medicine.disease ,Molecular Biology ,Pathology and Forensic Medicine ,Low-grade fibromyxoid sarcoma ,Highly sensitive - Published
- 2011
12. The t(X;6) in subungual exostosis results in transcriptional deregulation of the gene for insulin receptor substrate 4
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Piero Picci, Maria Debiec-Rychter, Antonio R. Perez-Atayde, Nils Mandahl, Raphael Sciot, Fredrik Mertens, Emely Möller, and Ignace Samson
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Collagen Type XII ,Osteochondroma ,Cancer Research ,Transcription, Genetic ,Bone Neoplasms ,Subungual exostosis ,Biology ,Collagen Type I ,Translocation, Genetic ,Nail Diseases ,Insulin Receptor Substrate 4 ,Gene expression ,medicine ,Humans ,Exostoses ,Receptor ,Regulation of gene expression ,Chromosomes, Human, X ,medicine.diagnostic_test ,medicine.disease ,Collagen Type I, alpha 1 Chain ,Gene Expression Regulation, Neoplastic ,Insulin receptor ,Oncology ,Regulatory sequence ,Insulin Receptor Substrate Proteins ,Cancer research ,biology.protein ,Chromosomes, Human, Pair 6 ,Fluorescence in situ hybridization - Abstract
Subungual exostosis is a benign bone- and cartilage-forming tumor known to harbor a pathognomonic t(X;6)(q22;q13-14). Using global gene expression analysis and quantitative real-time PCR, we could show that this translocation results in increased expression of the IRS4 gene, presumably due to disruption and/or exchange of regulatory sequences with the translocation partner, the COL12A1 gene. A corresponding deregulation at the protein level could be demonstrated in primary cell cultures using a combination of fluorescence in situ hybridization and immunostaining. As the t(X;6) usually is the sole cytogenetic aberration in subungual exostosis, the deregulated expression of IRS4 is likely to be pathogenetically essential. The exact role of IRS4 is still poorly investigated, but IRS proteins are known to act as mediators of signaling from receptors, such as the insulin and insulin-like growth factor 1 receptors, and thus have an important effect on cell growth and survival.
- Published
- 2010
13. POU5F1 , encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands
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Ioannis Panagopoulos, Emely Möller, J. J. Van Den Oord, Lena Mölne, Otte Brosjö, Nils Mandahl, Fredrik Mertens, Göran Stenman, and H Hamberg
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Genetics ,Homeobox protein NANOG ,Salivary gland ,Hidradenoma ,Biology ,Oct-4 ,medicine.disease ,Fusion protein ,Pathology and Forensic Medicine ,Cell biology ,Fusion gene ,medicine.anatomical_structure ,Mucoepidermoid carcinoma ,medicine ,Stem cell - Abstract
The EWSR1 gene is known to play a crucial role in the development of a number of different bone and soft tissue tumours, notably Ewing's sarcoma. POU5F1 is expressed during early development to maintain the totipotent status of embryonic stem and germ cells. In the present study, we report the fusion of EWSR1 and POU5F1 in two types of epithelial tumours: hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. This finding not only broadens considerably the spectrum of neoplasms associated with EWSR1 fusion genes but also strengthens the evidence for shared pathogenetic mechanisms in the development of adnexal and salivary gland tumours. Reminiscent of the previously reported fusion genes involving EWSR1, the identified transcript is predicted to encode a chimeric protein consisting of the EWSR1 amino-terminal domain and the POU5F1 carboxy-terminal domain. We assessed the transcriptional activation potential of the chimera compared to the wild-type proteins, as well as activation of transcription through the oct/sox composite element known to bind POU5F1. Among other POU5F1 target genes, this element is present in the promoter of NANOG and in the distal enhancer of POU5F1 itself. Our results show that although the chimera is capable of significant transcriptional activation, it may in fact convey a negative regulatory effect on target genes.
- Published
- 2008
14. High-resolution molecular cytogenetic analysis of Wilms tumors highlights diagnostic difficulties among small round cell kidney tumors
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Ingrid Øra, Emely Möller, Fredrik Mertens, Jan Alumets, Bengt Sandstedt, David Gisselsson, Johannes Hm Merks, Ioannis Panagopoulos, Yuesheng Jin, Ylva Stewénius, Jan de Kraker, Måns Åkerman, Oncogenomics, Cancer Center Amsterdam, and Paediatric Oncology
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Adult ,Cancer Research ,medicine.medical_specialty ,Oncogene Proteins, Fusion ,Ubiquitin-Protein Ligases ,Chromosomal translocation ,Biology ,Bioinformatics ,Wilms Tumor ,Translocation, Genetic ,Renal neoplasm ,Diagnosis, Differential ,Pathognomonic ,Genetics ,medicine ,Tumor Cells, Cultured ,Chromosomes, Human ,Humans ,RNA, Messenger ,RNA, Neoplasm ,Child ,Gene ,In Situ Hybridization, Fluorescence ,Chromosome Aberrations ,Proto-Oncogene Protein c-fli-1 ,Reverse Transcriptase Polymerase Chain Reaction ,Infant ,Wilms' tumor ,Telomere ,Subtelomere ,medicine.disease ,Kidney Neoplasms ,Chromosome Banding ,FLI1 ,Child, Preschool ,Karyotyping ,Cancer research ,Medical genetics ,RNA-Binding Protein EWS ,Transcription Factors - Abstract
Many solid tumors exhibit characteristic gene fusions, which are reflected by balanced translocations at the cytogenetic level. These changes might be useful diagnostic and prognostic tools. In Wilms tumor (WT, nephroblastoma) no fusions genes or recurrent balanced translocations have been described thus far. To screen for cryptic balanced translocations, we have analyzed 17 renal neoplasms, histopathologically classified as WT, by a combination of G-banding, multicolor FISH, and subtelomeric FISH. This approach revealed several submicroscopic chromosomal aberrations and three different seemingly balanced translocations, resulting in a heterozygous deletion of HACE1, an EWSR1/ERG fusion, and an EWSR1/FLI1 fusion, respectively. As EWSR1 rearrangements are known to be a characteristic of Ewing tumors (ET), our findings illustrate the diagnostic problems regarding small cell kidney tumors and strongly argue for the need of adjuvant diagnostic techniques in this group of neoplasms. In summary, our genomic screening approach proved efficient in finding structural chromosomal aberrations. The fact that no recurrent translocations were found in the WTs of this study argues against the presence of a frequent pathognomonic translocation in this disease entity. (c) 2008 Wiley-Liss, Inc. (Less)
- Published
- 2008
15. Molecular identification ofCOL6A3-CSF1 fusion transcripts in tenosynovial giant cell tumors
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Nils Mandahl, Fredrik Mertens, Ioannis Panagopoulos, and Emely Möller
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Adult ,Male ,Cancer Research ,Adolescent ,Oncogene Proteins, Fusion ,Molecular Sequence Data ,Chromosomal translocation ,Collagen Type VI ,Biology ,Translocation, Genetic ,Fusion gene ,Exon ,Genetics ,Humans ,RNA, Messenger ,Giant Cell Tumors ,Child ,Receptor ,Gene ,Aged ,Fusion ,Base Sequence ,Macrophage Colony-Stimulating Factor ,Synovial Membrane ,Breakpoint ,Middle Aged ,Molecular biology ,Chromosomes, Human, Pair 1 ,Chromosomes, Human, Pair 2 ,Female - Abstract
Tenosynovial giant cell tumors (TGCTs) are benign lesions of the tendon sheaths that primarily affect the fingers, ankles, or feet. Cytogenetic data have shown that 1p13 is most frequently involved in structural aberrations and that 2q37 is its most common translocation partner. The genes involved in the translocation t(1;2)(p13;q37) were recently identified: the colony-stimulating factor-1 (CSF1 or M-CSF1) at 1p13 and the collagen type VI alpha-3 (COL6A3) at 2q37. Based upon the suggestion that a fusion of these genes through the translocation would result in overexpression of CSF1 due to a strong COL6A3 promoter, we performed RT-PCR on six TGCT cases with t(1;2) to search for a putative COL6A3-CSF1 fusion gene. Such fusion transcripts were detected in three cases of which one was an in-frame fusion. In all cases, however, the breakpoints in CSF1 appeared downstream of exon 5, indicating that the amino-terminal part of CSF1, which interacts with its receptor CSF1R, is not encoded by the the chimeric transcripts we identified. The pathogenetic mechanism of these chimeric transcripts is therefore unclear.
- Published
- 2007
16. Characterization of the native CREB3L2 transcription factor and the FUS/CREB3L2 chimera
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Ioannis Panagopoulos, Fredrik Mertens, Nils Mandahl, Alexios Vlamis-Gardikas, Emely Möller, Margareth Isaksson, and Anna Dahlén
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Cancer Research ,Molecular Sequence Data ,Mutant Chimeric Proteins ,Nerve Tissue Proteins ,Biology ,Cell Line ,Mice ,Genetics ,Animals ,Humans ,Amino Acid Sequence ,Northern blot ,Cyclic AMP Response Element-Binding Protein ,Endoplasmic Reticulum Chaperone BiP ,Gene ,Transcription factor ,Peptide sequence ,Messenger RNA ,Sequence Homology, Amino Acid ,bZIP domain ,Molecular biology ,Transmembrane domain ,Basic-Leucine Zipper Transcription Factors ,NIH 3T3 Cells ,RNA-Binding Protein FUS - Abstract
CREB3L2 was first identified as the 3'-partner of FUS in a fusion gene that seems to be specific for low grade fibromyxoid sarcoma. In silico analyses suggest that the predicted CREB3L2 protein is a member of the CREB3 family of transcription factors, with its bZIP domain being highly similar to that in CREB3L1, CREB3L3, CREB3L4, CREB3, and Drosophila Bbf-2. In the present study, the authors assessed various cellular outcomes after transfection of NIH3T3 and HEK-293 cells with constructs containing full-length and truncated versions of CREB3L2 and FUS/CREB3L2. Northern blot of CREB3L2 mRNA revealed a 7.4 kbp band that contains 0.4 kbp and 5.5 kbp untranslated 5' and 3' regions, respectively. CREB3L2 constructs containing the first 120 amino acids (aa) showed the highest transcriptional activation. Much stronger transcriptional activation was consistently seen for the FUS/CREB3L2 constructs than for the corresponding CREB3L2 constructs. Transcriptional activity was achieved through the box-B element, ATF6 and CRE binding sites, as well as the GRP78 promoter. Proteins encoded by full-length CREB3L2 and FUS/CREB3L2 were localized to reticular structures of the cytoplasm, whereas the corresponding, truncated proteins lacking the transmembrane domain and the carboxy-terminal part of CREB3L2 resided within the nucleus. The results of the present study show that CREB3L2 is not only structurally, but also functionally very similar to CREB3L1. Thus, studies regarding the pathways influenced by wild-type CREB3L2 should provide valuable clues to the pathogenetic significance of the FUS/CREB3L2 chimera in low grade fibromyxoid sarcoma.
- Published
- 2006
17. Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes
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Karolin Hansén Nord, Fredrik Mertens, Maria Debiec-Rychter, Henryk A. Domanski, Emely Möller, Fredrik Vult von Steyern, Adrián Mariño-Enríquez, Christopher D.M. Fletcher, Yuesheng Jin, Jenny Nilsson, Nils Mandahl, Linda Magnusson, and Raf Sciot
- Subjects
Adult ,Male ,Cancer Research ,Aryl hydrocarbon receptor nuclear translocator ,Adolescent ,Repressor ,Abnormal Karyotype ,Aryl hydrocarbon receptor repressor ,Soft Tissue Neoplasms ,Angiofibroma ,Translocation, Genetic ,Chromosome Breakpoints ,Nuclear Receptor Coactivator 2 ,Young Adult ,Gene Order ,Genetics ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Oncogene Fusion ,RNA, Messenger ,Child ,Transcription factor ,Aged ,Aged, 80 and over ,biology ,Base Sequence ,Gene Expression Profiling ,Middle Aged ,Aryl hydrocarbon receptor ,Fusion protein ,Cell biology ,Chromosome Banding ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,biology.protein ,Nuclear receptor coactivator 2 ,Chromosomes, Human, Pair 5 ,Female ,Chromosomes, Human, Pair 8 - Abstract
Soft tissue angiofibroma is a recently delineated tumor type of unknown cellular origin. Cytogenetic analysis of four cases showed that they shared a t(5;8)(p15;q13). In three of them it was the sole change, underlining its pathogenetic significance. FISH mapping suggested the involvement of the aryl hydrocarbon receptor repressor (AHRR) and nuclear receptor coactivator 2 (NCOA2) genes in 5p15 and 8q13, respectively. RT-PCR revealed in-frame AHRR/NCOA2 and NCOA2/AHHR transcripts in all four cases. Interphase FISH on paraffin-embedded tissue from 10 further cases without cytogenetic data showed that three were positive for fusion of AHRR and NCOA2. While AHRR has never been implicated in gene fusions before, NCOA2 is the 3'-partner in fusions with MYST3 and ETV6 in leukemias and with PAX3 and HEY1 in sarcomas. As in the previously described fusion proteins, NCOA2 contributes with its two activation domains to the AHRR/NCOA2 chimera, substituting for the repressor domain of AHRR. Because the amino terminal part of the transcription factor AHRR, responsible for the recognition of xenobiotic response elements in target genes and for heterodimerization, shows extensive homology with the aryl hydrocarbon receptor (AHR), the fusion is predicted to upregulate the AHR/ARNT signaling pathway. Indeed, global gene expression analysis showed upregulation of CYP1A1 as well as other typical target genes of this pathway, such as those encoding toll-like receptors. Apart from providing a diagnostic marker for soft tissue angiofibroma, the results also suggest that this tumor constitutes an interesting model for evaluating the cellular effects of AHR signaling. © 2012 Wiley Periodicals, Inc. ispartof: Genes, Chromosomes & Cancer vol:51 issue:5 pages:510-520 ispartof: location:United States status: published
- Published
- 2011
18. Fusion of the FUS and CREB3L2 genes in a supernumerary ring chromosome in low-grade fibromyxoid sarcoma
- Author
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Anna Collin, Hammurabi Bartuma, Emely Möller, Fredrik Vult von Steyern, Henryk A. Domanski, Fredrik Mertens, and Nils Mandahl
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Male ,Cancer Research ,Lung Neoplasms ,Oncogene Proteins, Fusion ,Fibrosarcoma ,Ring chromosome ,Chromosomal translocation ,Biology ,Translocation, Genetic ,Low-grade fibromyxoid sarcoma ,Fusion gene ,Genetics ,medicine ,Humans ,Supernumerary ,Ring Chromosomes ,Molecular Biology ,In Situ Hybridization, Fluorescence ,Aged ,medicine.diagnostic_test ,Karyotype ,medicine.disease ,Molecular biology ,Orthopedics ,Basic-Leucine Zipper Transcription Factors ,Cancer and Oncology ,Karyotyping ,Cancer research ,RNA-Binding Protein FUS ,Sarcoma ,Medical Genetics ,Chromosomes, Human, Pair 16 ,Chromosomes, Human, Pair 7 ,Fluorescence in situ hybridization - Abstract
Low-grade fibromyxoid sarcoma (LGFMS) is a rare, low-grade malignant soft tissue tumor that is often mistaken for either benign or more malignant tumor types. Commonly, this tumor affects young adults and typically arises in the deep proximal extremities or trunk with frequent recurrences and can metastasize to the lungs many years later. Most cases have a recurrent balanced translocation involving chromosomes 7 and 16, t(7;16)(q32-34;p11), which leads to the fusion of the FUS and CREB3L2 genes. However, supernumerary ring chromosomes have been identified in a subset of FUS/CREB3L2-positive LGFMS, but it has not yet been formally demonstrated that such ring chromosomes harbor the FUS/CREB3L2 fusion gene. Here, we report the genetic findings of a supernumerary ring chromosome from an LGFMS from a 77-year-old man. Chromosome banding analysis revealed a supernumerary ring chromosome, and further studies with fluorescence in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the ring contained material from chromosomes 7 and 16, that the FUS gene was present in two rearranged copies, and that it expressed the FUS/CREB3L2 fusion gene. Moreover, an assessment of previously reported cases showed that tumors with ring chromosomes relapsed more often than tumors with a balanced t(7;16), suggesting that ring formation in LGFMS is correlated with tumor progression.
- Published
- 2009
19. Bidirectionality and transcriptional activity of the EWSR1 promoter region
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Fredrik Mertens, Emely Möller, Mariola Iliszko, Nils Mandahl, and Ioannis Panagopoulos
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Cancer Research ,Transcription, Genetic ,Molecular Sequence Data ,Bone Neoplasms ,Sarcoma, Ewing ,Chimeric gene ,Biology ,Transfection ,Transcription (biology) ,Sequence Homology, Nucleic Acid ,Transcriptional regulation ,Animals ,Humans ,Promoter Regions, Genetic ,Gene ,Conserved Sequence ,Regulation of gene expression ,Reporter gene ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,RNA-Binding Proteins ,Promoter ,General Medicine ,Fusion protein ,Molecular biology ,Neoplasm Proteins ,Gene Expression Regulation ,Oncology ,Calmodulin-Binding Proteins ,RNA-Binding Protein EWS ,Apoptosis Regulatory Proteins - Abstract
EWSR1 is involved in chimeric proteins which play crucial roles in the development of a variety of bone and soft tissue tumors. Many of the chimeric genes involving EWSR1 have been extensively studied, whereas less is known about the wild-type (wt) gene and its regulation. As the expression of the chimeric gene is driven by the EWSR1 promoter, it is of importance to study the mechanisms regulating wt EWSR1 expression. We estimated the transcriptional activity of the EWSR1 promoter through deletion fragments driving reporter gene expression. This assay identified the 100-bp region immediately downstream of the EWSR1 transcriptional start site (+1) and the downstream region from +100 to +300 as important regions for transcriptional regulation. We also found that EWSR1 and RHBDD3, a gene located directly upstream of EWSR1 that is likely to share regulatory elements with EWSR1, were co-expressed in the tissue panels, Ewing tumor biopsies and cell lines. Thus, our results show that the EWSR1 promoter functions in a bidirectional manner, thereby regulating also RHBDD3, and identifies specific regions that strongly influence promoter activity.
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- 2009
20. Low frequency of EWSR1 rearrangements in neoplasms classified as high-risk Wilms tumors
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Ingrid Øra, Ylva Stewénius, David Gisselsson, Margareth Isaksson, Johannes Bras, Emely Möller, Ildikó Frigyesi, Bengt Sandstedt, Jan Alumets, Pathology, and Oncogenomics
- Subjects
Oncology ,Gene Rearrangement ,medicine.medical_specialty ,Pediatrics ,business.industry ,RNA-Binding Proteins ,Hematology ,Wilms Tumor ,Kidney Neoplasms ,Text mining ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Humans ,Calmodulin-Binding Proteins ,RNA-Binding Protein EWS ,business - Published
- 2009
21. A PCR/restriction digestion assay for the detection of the transcript variants 1 and 2 of POU5F1
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Ioannis Panagopoulos, Margareth Isaksson, Emely Möller, and Fredrik Mertens
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Adult ,Male ,Cancer Research ,Adolescent ,Pseudogene ,Molecular Sequence Data ,Dysgerminoma ,Biology ,Genome ,chemistry.chemical_compound ,Exon ,Sequence Homology, Nucleic Acid ,Testis ,Genetics ,Leukocytes ,Humans ,Protein Isoforms ,False Positive Reactions ,RNA, Messenger ,Ovarian Neoplasms ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,RNA ,DNA ,Molecular biology ,Peripheral blood ,Restriction site ,Alternative Splicing ,chemistry ,Restriction digest ,Female ,Artifacts ,Octamer Transcription Factor-3 ,Sequence Alignment ,Polymorphism, Restriction Fragment Length ,Pseudogenes - Abstract
POU5F1 has two alternatively spliced transcripts: a long (variant 1, NM_002701) and a short (variant 2, NM_203289) transcript. Only variant 1 is a key regulator of pluripotency. Hence, it is important to be able to distinguish this transcript from variant 2 and from the many pseudogenes present in the genome. Previous studies on the expression of POU5F1 were, however, usually carried out without considering the existence of the two transcripts and the pseudogenes which could be the source of false positive RT-PCR amplification. Here, we establish an RT-PCR/restriction digestion analysis to distinguish variant 1 of POU5F1 from variant 2 and all its currently known pseudogenes. Variant 1 has ApaI and Tsp45I restriction sites, which are not present in the pseudogenes or in variant 2. Thus, ApaI- and Tsp45I- digestions of POU5F1 PCR fragment, amplified with primers flanking these sites, are sufficient to identify the true variant 1 of POU5F1. To study the expression of variant 2 of POU5F1, two forward primers in the 5'-region that are not present in variant 1 were combined with reverse primers located in exon 3 of POU5F1 common to both transcripts. The assay was applied on 10 samples from peripheral blood leukocytes and commercially available ready-cDNAs from leukocytes and testis. We found that only variant 2 was expressed in leukocytes and testis and that the extracted RNA was not completely DNA free, despite DNAse treatment. This trace amount of DNA is a source of false positive RT-PCR amplifications. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. (c) 2008 Wiley-Liss, Inc. (Less)
- Published
- 2008
22. Comparison of the proximal promoter regions of the PAX3 and PAX7 genes
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Emely Möller, Fredrik Mertens, Ioannis Panagopoulos, Nils Mandahl, and Margareth Isaksson
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Cancer Research ,Transcription, Genetic ,PAX3 ,Biology ,Transfection ,3T3 cells ,Translocation, Genetic ,Cell Line ,Fusion gene ,Mice ,Plasmid ,Genes, Reporter ,Rhabdomyosarcoma ,Genetics ,medicine ,Animals ,Humans ,Paired Box Transcription Factors ,Child ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,PAX3 Transcription Factor ,DNA Primers ,Chromosome Aberrations ,Reporter gene ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Amplification ,PAX7 Transcription Factor ,3T3 Cells ,musculoskeletal system ,medicine.disease ,Molecular biology ,medicine.anatomical_structure ,embryonic structures ,Alveolar rhabdomyosarcoma ,tissues ,HeLa Cells ,Plasmids - Abstract
Translocations t(2;13)(q35;q14) and t(1;13)(p36;q14), which fuse PAX3 and PAX7, respectively, to FOXO1A, characterize alveolar rhabdomyosarcoma. Previous studies have suggested that the expression of PAX7-FOXO1A is copy-number dependent, but that of PAX3-FOXO1A is not, which may be due to a weaker PAX7 than PAX3 promoter. The aim of the present study was to compare the transcriptional activities of the PAX3 and PAX7 proximal promoter regions, using the dual-luciferase reporter assay with three vector systems in eight cell lines. The PAX3 promoter was found to have higher transcriptional activity than that of PAX7 irrespective of the vector system or cell line used. These findings are consistent with the idea that an amplification event is required for the PAX7-FOXO1A chimeric transcript to reach a critical expression level.
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- 2007
23. The POU5F1P1 pseudogene encodes a putative protein similar to POU5F1 isoform 1
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Ioannis Panagopoulos, Emely Möller, Anna Collin, and Fredrik Mertens
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Genetics ,Gene isoform ,Regulation of gene expression ,Cancer Research ,Oncology ,Activator (genetics) ,Pseudogene ,Transcriptional regulation ,Sequence alignment ,General Medicine ,Biology ,Peptide sequence ,Gene - Abstract
POU5F1, which encodes a transcriptional factor, has two alternatively spliced transcripts, 1 and 2, as well as six pseudogenes. Transcript 1 is considered to be a key regulator of cellular pluripotency and self-renewal. The POU5F1 pseudogene, POU5F1P1 on 8q24, encodes a protein with 95% homology with the isoform 1 of POU5F1. It is located 15 kbp downstream of the SNP rs6983267, which is strongly associated with an increased risk of prostate and colon cancer, and within the amplified region in a variety of human malignancies. The previous finding of expressed sequence tags suggests that POU5F1P1 can be expressed. We showed that a putative POU5F1P1 protein is localized in the nucleus, acts as a transcriptional activator and regulates the expression in a similar way to the POU5F1 isoform 1. However, POU5F1P1 was a weaker activator than isoform 1 of POU5F1, possibly due to the amino acid substitutions.
- Published
- 1994
24. Characterization of the native CREB3L2 transcription factor and the FUS/CREB3L2 chimera.
- Author
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Ioannis Panagopoulos, Emely Möller, Anna Dahlén, Margareth Isaksson, Nils Mandahl, Alexios Vlamis‐Gardikas, and Fredrik Mertens
- Published
- 2007
- Full Text
- View/download PDF
25. Chapter 38 Immunological aspects of neural grafting in the mammalian central nervous system
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Håkan Widner, Anders Björklund, Patrik Brundin, and Emely Möller
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medicine.medical_treatment ,Central nervous system ,Graft vs Host Reaction ,Immunosuppression ,Mhc antigens ,Biology ,Blood–brain barrier ,Major histocompatibility complex ,surgical procedures, operative ,medicine.anatomical_structure ,Neural grafting ,Immunology ,medicine ,biology.protein ,Homing (hematopoietic) - Abstract
Publisher Summary This chapter discusses the immunological aspects of neural grafting in the mammalian central nervous system. The central nervous system (CNS) tissue, under normal conditions, seems to express low levels of MHC antigens; however, the available data indicate that they may be expressed under certain circumstances. This chapter describes various immunological aspects of neural grafting in the mammalian central nervous system. There seems to be no correlation between macromolecular leakage across the blood-brain barrier (BBB) and xenograft rejection, as a later rejection can occur after withdrawal of immunosuppression, when BBB function is restored. Although, a BBB may be formed in neural grafts, the origin of vessels, the expression of donor type major histocompatibility complex (MHC) structures on the vessels and the presence of homing structures for lymphocytes on the vessels in the graft area are likely to be relevant factors for graft rejection. Intracerebral neural xenografts generally fail unless the hosts are immunosuppressed, whereas the present allografts survive in all of the grafted mice, for up to six to seven weeks, without immunosuppression. The long-term allograft survival under these conditions is difficult to explain, and clearly requires further investigation.
- Published
- 1988
26. Survival and immunogenicity of dissociated allogeneic fetal neural dopamine-rich grafts when implanted into the brains of adult mice
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Emely Möller, Håkan Widner, Anders Björklund, and Patrik Brundin
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Male ,Pathology ,medicine.medical_specialty ,Dopamine ,Spleen ,Striatum ,Major histocompatibility complex ,Mice ,Immune system ,Histocompatibility Antigens ,medicine ,Animals ,Transplantation, Homologous ,Mice, Inbred C3H ,Fetus ,biology ,General Neuroscience ,Immunogenicity ,Graft Survival ,Brain ,Corpus Striatum ,Histocompatibility ,Mice, Inbred C57BL ,Transplantation ,surgical procedures, operative ,medicine.anatomical_structure ,Immune System ,Mice, Inbred CBA ,biology.protein ,Female - Abstract
The survival of grafts of dissociated allogeneic fetal neural dopamine (DA) rich tissue in the striatum has been studied after transplantation between inbred strains of mice differing at defined immunogenetical loci between donor and recipient. Six to 7 weeks and 15 weeks after grafting, surviving grafted DA neurons were found in the brains of all the recipients, albeit with a large variation in numbers, located either within the striatum or within the adjacent lateral ventricle. The mean number of surviving DA neurons did not differ between the syngeneic controls and the histoincompatible donor-host combinations, and there was no difference in survival between grafts that differed at single or multiple major histocompatibility complex (MHC) loci, and those that differed at multiple non-MHC loci. The amount of inflammatory cells in the graft area did not differ between the groups, and none of the animals showed massive infiltration of inflammatory cells. The in situ immunogenicity of the grafted neural tissue after intracerebral implantation was monitored by means of Simonsen's alloimmunization test, at 6-7 weeks after transplantation, which provides a sensitive measure primarily of the cellular immunological response. Most, but not all, graft recipients showed immunization with a Spleen Index (S.I.) close to that seen in recipients of an orthotopical skin graft of the same histoincompatibility combination. In contrast to the prolonged survival of the intracerebral neural transplants, none of the skin grafts survived longer than 3 weeks, thus demonstrating the immunologically privileged status of the brain. We conclude that intracerebrally grafted allogeneic neural tissue is capable of provoking a cellular immune response. Despite host immunization, however, the dissociated fetal neural allografts survived for at least 15 weeks without any overt signs of rejection, regardless of the donor-host combination used.
- Published
- 1989
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