14 results on '"Scherezade Jiménez"'
Search Results
2. Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma
- Author
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Bruna Calsina, Elena Piñeiro-Yáñez, Ángel M. Martínez-Montes, Eduardo Caleiras, Ángel Fernández-Sanromán, María Monteagudo, Rafael Torres-Pérez, Coral Fustero-Torre, Marta Pulgarín-Alfaro, Eduardo Gil, Rocío Letón, Scherezade Jiménez, Santiago García-Martín, Maria Carmen Martin, Juan María Roldán-Romero, Javier Lanillos, Sara Mellid, María Santos, Alberto Díaz-Talavera, Ángeles Rubio, Patricia González, Barbara Hernando, Nicole Bechmann, Margo Dona, María Calatayud, Sonsoles Guadalix, Cristina Álvarez-Escolá, Rita M. Regojo, Javier Aller, Maria Isabel Del Olmo-Garcia, Adrià López-Fernández, Stephanie M. J. Fliedner, Elena Rapizzi, Martin Fassnacht, Felix Beuschlein, Marcus Quinkler, Rodrigo A. Toledo, Massimo Mannelli, Henri J. Timmers, Graeme Eisenhofer, Sandra Rodríguez-Perales, Orlando Domínguez, Geoffrey Macintyre, Maria Currás-Freixes, Cristina Rodríguez-Antona, Alberto Cascón, Luis J. Leandro-García, Cristina Montero-Conde, Giovanna Roncador, Juan Fernando García-García, Karel Pacak, Fátima Al-Shahrour, and Mercedes Robledo
- Subjects
Science - Abstract
The molecular mechanisms underlying metastasis in pheochromocytoma/paraganglioma (mPPGL) remain to be explored. Here, the authors perform genomic and immunogenomic profiling of mPPGL tumors and suggest potential biomarkers for risk of metastasis and immunotherapy response.
- Published
- 2023
- Full Text
- View/download PDF
3. CD229 (Ly9) a Novel Biomarker for B-Cell Malignancies and Multiple Myeloma
- Author
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Giovanna Roncador, Joan Puñet-Ortiz, Lorena Maestre, Luis Gerardo Rodríguez-Lobato, Scherezade Jiménez, Ana Isabel Reyes-García, Álvaro García-González, Juan F. García, Miguel Ángel Piris, Santiago Montes-Moreno, Manuel Rodríguez-Justo, Mari-Pau Mena, Carlos Fernández de Larrea, and Pablo Engel
- Subjects
leukemia ,lymphoma ,myeloma ,B cells ,CD229 ,Ly9 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
CD229 (Ly9) homophilic receptor, which belongs to the SLAM family of cell-surface molecules, is predominantly expressed on B and T cells. It acts as a signaling molecule, regulating lymphocyte homoeostasis and activation. Studies of CD229 function indicate that this receptor functions as a regulator of the development of marginal-zone B cells and other innate-like T and B lymphocytes. The expression on leukemias and lymphomas remains poorly understood due to the lack of CD229 monoclonal antibodies (mAb) for immunohistochemistry application (IHC). In this study, we used a new mAb against the cytoplasmic region of CD229 to study the expression of CD229 on normal tissues and B-cell malignancies, including multiple myeloma (MM), using tissue microarrays. We showed CD229 to be restricted to hematopoietic cells. It was strongly expressed in all cases of MM and in most marginal-zone lymphomas (MZL). Moderate CD229 expression was also found in chronic lymphocyte leukemia (CLL), follicular (FL), classic mantle-cell (MCL) and diffuse large B-cell lymphoma. Given the high expression on myeloma cells, we also analyzed for the presence of soluble CD229 in the sera of these patients. Serum levels of soluble CD229 (sCD229) at the time of diagnosis in MM patients could be useful as a prognostic biomarker. In conclusion, our results indicate that CD229 represents not only a useful biomarker but also an attractive therapeutic target.
- Published
- 2022
- Full Text
- View/download PDF
4. High-mobility group box (TOX) antibody a useful tool for the identification of B and T cell subpopulations.
- Author
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Lorena Maestre, Juan Fernando García-García, Scherezade Jiménez, Ana Isabel Reyes-García, Álvaro García-González, Santiago Montes-Moreno, Alberto J Arribas, Patricia González-García, Eduardo Caleiras, Alison H Banham, Miguel Ángel Piris, and Giovanna Roncador
- Subjects
Medicine ,Science - Abstract
Thymocyte selection-associated high-mobility group box (TOX) is a DNA-binding factor that is able to regulate transcription by modifying local chromatin structure and modulating the formation of multi-protein complexes. TOX has multiple roles in the development of the adaptive immune system including development of CD4 T cells, NK cells and lymph node organogenesis. However very few antibodies recognizing this molecule have been reported and no extensive study of the expression of TOX in reactive and neoplastic lymphoid tissue has been performed to date. In the present study, we have investigated TOX expression in normal and neoplastic lymphoid tissues using a novel rat monoclonal antibody that recognizes its target molecule in paraffin-embedded tissue sections. A large series of normal tissues and B- and T-cell lymphomas was studied, using whole sections and tissue microarrays. We found that the majority of precursor B/T lymphoblastic, follicular and diffuse large B-cell lymphomas, nodular lymphocyte-predominant Hodgkin lymphomas and angioimmunoblastic T-cell lymphomas strongly expressed the TOX protein. Burkitt and mantle cell lymphomas showed TOX expression in a small percentage of cases. TOX was not found in the majority of chronic lymphocytic leukemia, myelomas, marginal zone lymphomas and classical Hodgkin lymphomas. In conclusion, we describe for the first time the expression of TOX in normal and neoplastic lymphoid tissues. The co-expression of TOX and PD-1 identified in normal and neoplastic T cells is consistent with recent studies identifying TOX as a critical regulator of T-cell exhaustion and a potential immunotherapy target. Its differential expression may be of diagnostic relevance in the differential diagnosis of follicular lymphoma, the identification of the phenotype of diffuse large B-cell lymphoma and the recognition of peripheral T-cell lymphoma with a follicular helper T phenotype.
- Published
- 2020
- Full Text
- View/download PDF
5. Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma
- Author
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María Monteagudo, Paula Martínez, Luis J. Leandro-García, Ángel M. Martínez-Montes, Bruna Calsina, Marta Pulgarín-Alfaro, Alberto Díaz-Talavera, Sara Mellid, Rocío Letón, Eduardo Gil, Manuel Pérez-Martínez, Diego Megías, Raúl Torres-Ruiz, Sandra Rodriguez-Perales, Patricia González, Eduardo Caleiras, Scherezade Jiménez-Villa, Giovanna Roncador, Cristina Álvarez-Escolá, Rita M. Regojo, María Calatayud, Sonsoles Guadalix, Maria Currás-Freixes, Elena Rapizzi, Letizia Canu, Svenja Nölting, Hanna Remde, Martin Fassnacht, Nicole Bechmann, Graeme Eisenhofer, Massimo Mannelli, Felix Beuschlein, Marcus Quinkler, Cristina Rodríguez-Antona, Alberto Cascón, María A. Blasco, Cristina Montero-Conde, and Mercedes Robledo
- Subjects
pheochromocytoma ,paraganglioma ,PPGL ,telomeres ,TERT ,ATRX ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients.
- Published
- 2021
- Full Text
- View/download PDF
6. CSF1R Protein Expression in Reactive Lymphoid Tissues and Lymphoma: Its Relevance in Classical Hodgkin Lymphoma.
- Author
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Ana M Martín-Moreno, Giovanna Roncador, Lorena Maestre, Elena Mata, Scherezade Jiménez, Jorge L Martínez-Torrecuadrada, Ana I Reyes-García, Carmen Rubio, José F Tomás, Mónica Estévez, Karen Pulford, Miguel A Piris, and Juan F García
- Subjects
Medicine ,Science - Abstract
Tumour-associated macrophages (TAMs) have been associated with survival in classic Hodgkin lymphoma (cHL) and other lymphoma types. The maturation and differentiation of tissue macrophages depends upon interactions between colony-stimulating factor 1 receptor (CSF1R) and its ligands. There remains, however, a lack of consistent information on CSF1R expression in TAMs. A new monoclonal antibody, FER216, was generated to investigate CSF1R protein distribution in formalin fixed tissue samples from 24 reactive lymphoid tissues and 187 different lymphoma types. We also analysed the distribution of CSF1R+, CD68+ and CD163+ macrophages by double immunostaining, and studied the relationship between CSF1R expression and survival in an independent series of 249 cHL patients. CSF1R+ TAMs were less frequent in B-cell lymphocytic leukaemia and lymphoblastic B-cell lymphoma than in diffuse large B-cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma and cHL. HRS cells in cHL and, with the exception of three cases of anaplastic large cell lymphoma, the neoplastic cells in NHLs, lacked detectable CSF1R protein. A CSF1R+ enriched microenvironment in cHL was associated with shorter survival in an independent series of 249 cHL patients. CSF1R pathway activation was evident in the cHL and inactivation of this pathway could be a potential therapeutic target in cHL cases.
- Published
- 2015
- Full Text
- View/download PDF
7. Supplementary Figure S2 from Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas
- Author
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Alberto Cascón, Mercedes Robledo, Graeme Eisenhofer, Jorgina Satrústegui, Manel Esteller, Sebastian Moran, Lorena Maestre, Scherezade Jiménez, Emiliano Honrado, Rafael Torres-Pérez, Antonio Galarreta, Rocío Letón, Guillermo Pita, María Currás-Freixes, Laura Contreras, Susan Richter, Iñaki Comino-Méndez, and Laura Remacha
- Abstract
(A) GOT2 western blot of HeLa cells stably silenced for GOT2 expression by shRNA transfection compared to non-silenced scrambled (Scr) control cells. β-actin was used as a loading control. (B) Number of GOT2 KD HeLa cells after transfection with empty vector (EV), GOT2- WT cDNA, and GOT2- c.357A>T. Cells were seeded into 12-well plates and incubated for various times, as indicated. The counts are reported as means (n=3). A t-test was applied to test for differences. n.s.: not significant.
- Published
- 2023
8. Supplementary Table S1 from Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas
- Author
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Alberto Cascón, Mercedes Robledo, Graeme Eisenhofer, Jorgina Satrústegui, Manel Esteller, Sebastian Moran, Lorena Maestre, Scherezade Jiménez, Emiliano Honrado, Rafael Torres-Pérez, Antonio Galarreta, Rocío Letón, Guillermo Pita, María Currás-Freixes, Laura Contreras, Susan Richter, Iñaki Comino-Méndez, and Laura Remacha
- Abstract
Genes included in the targeted next-generation sequencing panel
- Published
- 2023
9. Supplementary Figure Legends from Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas
- Author
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Alberto Cascón, Mercedes Robledo, Graeme Eisenhofer, Jorgina Satrústegui, Manel Esteller, Sebastian Moran, Lorena Maestre, Scherezade Jiménez, Emiliano Honrado, Rafael Torres-Pérez, Antonio Galarreta, Rocío Letón, Guillermo Pita, María Currás-Freixes, Laura Contreras, Susan Richter, Iñaki Comino-Méndez, and Laura Remacha
- Abstract
Legends of the Supplementary Figures
- Published
- 2023
10. Data from Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas
- Author
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Alberto Cascón, Mercedes Robledo, Graeme Eisenhofer, Jorgina Satrústegui, Manel Esteller, Sebastian Moran, Lorena Maestre, Scherezade Jiménez, Emiliano Honrado, Rafael Torres-Pérez, Antonio Galarreta, Rocío Letón, Guillermo Pita, María Currás-Freixes, Laura Contreras, Susan Richter, Iñaki Comino-Méndez, and Laura Remacha
- Abstract
Purpose: Mutations in Krebs cycle genes are frequently found in patients with pheochromocytomas/paragangliomas. Disruption of SDH, FH or MDH2 enzymatic activities lead to accumulation of specific metabolites, which give rise to epigenetic changes in the genome that cause a characteristic hypermethylated phenotype. Tumors showing this phenotype, but no alterations in the known predisposing genes, could harbor mutations in other Krebs cycle genes.Experimental Design: We used downregulation and methylation of RBP1, as a marker of a hypermethylation phenotype, to select eleven pheochromocytomas and paragangliomas for targeted exome sequencing of a panel of Krebs cycle-related genes. Methylation profiling, metabolite assessment and additional analyses were also performed in selected cases.Results: One of the 11 tumors was found to carry a known cancer-predisposing somatic mutation in IDH1. A variant in GOT2, c.357A>T, found in a patient with multiple tumors, was associated with higher tumor mRNA and protein expression levels, increased GOT2 enzymatic activity in lymphoblastic cells, and altered metabolite ratios both in tumors and in GOT2 knockdown HeLa cells transfected with the variant. Array methylation-based analysis uncovered a somatic epigenetic mutation in SDHC in a patient with multiple pheochromocytomas and a gastrointestinal stromal tumor. Finally, a truncating germline IDH3B mutation was found in a patient with a single paraganglioma showing an altered α-ketoglutarate/isocitrate ratio.Conclusions: This study further attests to the relevance of the Krebs cycle in the development of PCC and PGL, and points to a potential role of other metabolic enzymes involved in metabolite exchange between mitochondria and cytosol. Clin Cancer Res; 23(20); 6315–24. ©2017 AACR.
- Published
- 2023
11. Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma
- Author
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Massimo Mannelli, Alberto Cascón, Sara Mellid, Marta Pulgarín-Alfaro, Mercedes Robledo, Alberto Díaz-Talavera, Luis J Leandro-García, Letizia Canu, Svenja Nölting, Sandra Rodriguez-Perales, Sonsoles Guadalix, Eduardo Caleiras, Raúl Torres-Ruiz, Patricia Gonzalez, María Calatayud, Cristina Montero-Conde, Scherezade Jiménez-Villa, Maria A. Blasco, Maria Currás-Freixes, Felix Beuschlein, Eduardo Gil, Nicole Bechmann, Giovanna Roncador, Hanna Remde, Graeme Eisenhofer, Paula Martinez, Martin Fassnacht, Diego Megías, Bruna Calsina, Marcus Quinkler, Cristina Rodríguez-Antona, Rita Maria Regojo, Rocío Letón, María Monteagudo, Ángel M Martínez-Montes, Elena Rapizzi, Cristina Álvarez-Escolá, Manuel Pérez-Martínez, and UAM. Departamento de Medicina
- Subjects
Cancer Research ,Prognostic biomarker ,Medicina ,ALT ,TERT ,Pheochromocytoma ,Biology ,Paraganglioma ,03 medical and health sciences ,paraganglioma ,0302 clinical medicine ,medicine ,PPGL ,ddc:610 ,prognostic biomarker ,Gene ,NOP10 ,RC254-282 ,ATRX ,030304 developmental biology ,0303 health sciences ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,telomeres ,Phenotype ,pheochromocytoma ,In vitro ,Telomere ,Telomeres ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry - Abstract
Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAM, One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients., This work was supported by Project PI17/01796 and PI20/01169 to M.R. [Instituto de Salud Carlos III (ISCIII), Acción Estratégica en Salud, cofinanciado a través del Fondo Europeo de Desarrollo Regional (FEDER)], Paradifference Foundation [no grant number applicable to M.R.] and Pheipas Association [no grant number applicable to M.R.]. Research in the M.A.B. lab was funded by the Spanish State Research Agency (AEI), Ministry of Science and Innovation, cofounded by the European Regional Development Fund (ERDF) (SAF2017-82623-R and SAF2015-72455-EXP), the Comunidad de Madrid Project (S2017/BMD-3770), the World Cancer Research (WCR) Project (16-1177), the European Research Council (ERC-AvG Shelterines GA882385) and the Fundación Botín (Spain). International collaborators research has been supported by the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease” to F.B., S.N., M.F.-C., N.B. and G.E. and by the Immuno-TargET project under the umbrella of the University Medicine Zurich to F.B. and S.N. M.M. was supported by the Spanish Ministry of Science, Innovation and Universities “Formación del Profesorado Universitario—FPU” fellowship with ID number FPU18/00064. L.J.L.-G. was supported both by the Banco Santander Foundation and La Caixa Postdoctoral Junior Leader Fellowship (LCF/BQ/PI20/11760011). C.M.-C. was supported by a grant from the AECC Foundation (AIO15152858 MONT). A.M.M.-M. was supported by CAM (S2017/BMD-3724; TIRONET2-CM). B.C. was supported by the Rafael del Pino Foundation (Becas de Excelencia Rafael del Pino 2017) and currently by the ISCIII project PI17/01796. A.D.-T. is supported by the Centro de Investigacion Biomédica en Red de Enfermedades Raras (CIBERER). We thank the Spanish National Tumor Bank Network (RD09/0076/00047) for the support in obtaining tumor samples and all patients, physicians and tumor biobanks involved in the study
- Published
- 2021
- Full Text
- View/download PDF
12. High-mobility group box (TOX) antibody a useful tool for the identification of B and T cell subpopulations
- Author
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Scherezade Jiménez, Miguel A. Piris, Patricia González-García, Alberto J. Arribas, Santiago Montes-Moreno, Lorena Maestre, Eduardo Caleiras, Giovanna Roncador, Alison H. Banham, Álvaro García-González, Juan Fernando García-García, Ana Isabel Reyes-García, European Commission, Comunidad de Madrid (España), Instituto de Salud Carlos III - ISCIII, Comunidad de Madrid, and Instituto de Salud Carlos III
- Subjects
0301 basic medicine ,Male ,B Cells ,Physiology ,Chronic lymphocytic leukemia ,Protein Expression ,Follicular lymphoma ,Gene Expression ,Hematologic Cancers and Related Disorders ,White Blood Cells ,Antibodies, Monoclonal, Murine-Derived ,Mice ,fluids and secretions ,0302 clinical medicine ,Animal Cells ,immune system diseases ,Antibody Specificity ,T-Lymphocyte Subsets ,Immune Physiology ,hemic and lymphatic diseases ,Medicine and Health Sciences ,Lymph node ,Staining ,Multidisciplinary ,T Cells ,High Mobility Group Proteins ,Cell Staining ,Hematology ,Marginal zone ,Thymocyte ,medicine.anatomical_structure ,Lymphatic system ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Lymphomas ,Female ,Cellular Types ,Anatomy ,Research Article ,Lymphoma, B-Cell ,Lymphoid Tissue ,Immune Cells ,Science ,T cell ,Immunology ,B-Lymphocyte Subsets ,Biology ,Research and Analysis Methods ,Lymphoma, T-Cell ,Lymphatic System ,03 medical and health sciences ,Cell Line, Tumor ,Gene Expression and Vector Techniques ,medicine ,Animals ,Humans ,RNA, Messenger ,Rats, Wistar ,Antibody-Producing Cells ,Molecular Biology Techniques ,Immunohistochemistry Techniques ,Molecular Biology ,Molecular Biology Assays and Analysis Techniques ,Blood Cells ,Biology and Life Sciences ,Cancers and Neoplasms ,Cell Biology ,medicine.disease ,Lymphoma ,Rats ,Histochemistry and Cytochemistry Techniques ,Mice, Inbred C57BL ,030104 developmental biology ,Specimen Preparation and Treatment ,Immunologic Techniques ,Cancer research ,bacteria ,Lymph Nodes ,Spleen - Abstract
Thymocyte selection-associated high-mobility group box (TOX) is a DNA-binding factor that is able to regulate transcription by modifying local chromatin structure and modulating the formation of multi-protein complexes. TOX has multiple roles in the development of the adaptive immune system including development of CD4 T cells, NK cells and lymph node organogenesis. However very few antibodies recognizing this molecule have been reported and no extensive study of the expression of TOX in reactive and neoplastic lymphoid tissue has been performed to date. In the present study, we have investigated TOX expression in normal and neoplastic lymphoid tissues using a novel rat monoclonal antibody that recognizes its target molecule in paraffin-embedded tissue sections. A large series of normal tissues and B- and T-cell lymphomas was studied, using whole sections and tissue microarrays. We found that the majority of precursor B/T lymphoblastic, follicular and diffuse large B-cell lymphomas, nodular lymphocyte-predominant Hodgkin lymphomas and angioimmunoblastic T-cell lymphomas strongly expressed the TOX protein. Burkitt and mantle cell lymphomas showed TOX expression in a small percentage of cases. TOX was not found in the majority of chronic lymphocytic leukemia, myelomas, marginal zone lymphomas and classical Hodgkin lymphomas. In conclusion, we describe for the first time the expression of TOX in normal and neoplastic lymphoid tissues. The co-expression of TOX and PD-1 identified in normal and neoplastic T cells is consistent with recent studies identifying TOX as a critical regulator of T-cell exhaustion and a potential immunotherapy target. Its differential expression may be of diagnostic relevance in the differential diagnosis of follicular lymphoma, the identification of the phenotype of diffuse large B-cell lymphoma and the recognition of peripheral T-cell lymphoma with a follicular helper T phenotype. This work was supported by grants from the Plan Nacional de I+D+I, co-financed by the ISCIII-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER), CIBERONC -CB16/12/00291 (MAP), and Programs of R&D activities among research groups of the Community of Madrid in Biomedicine (B2017/BMD-3778) (MAP, GR, JFGG). All funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí
- Published
- 2020
13. Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer-Predisposing Mutations in Pheochromocytomas and Paragangliomas
- Author
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Alberto Cascón, Rocío Letón, Laura Contreras, Maria Currás-Freixes, Jorgina Satrústegui, Sebastian Moran, Laura Remacha, Graeme Eisenhofer, Iñaki Comino-Méndez, Mercedes Robledo, Emiliano Honrado, Manel Esteller, Susan Richter, Lorena Maestre, Antonio Galarreta, Guillermo Pita, Rafael Torres-Pérez, and Scherezade Jiménez
- Subjects
0301 basic medicine ,Cancer Research ,IDH1 ,Citric Acid Cycle ,Pheochromocytoma ,Biology ,medicine.disease_cause ,Paraganglioma ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,medicine ,Cluster Analysis ,Humans ,Metabolomics ,Exome ,Genetic Predisposition to Disease ,Epigenetics ,Exome sequencing ,Genetic Association Studies ,Mutation ,Gene Expression Profiling ,Gene Expression Regulation, Developmental ,High-Throughput Nucleotide Sequencing ,DNA Methylation ,medicine.disease ,Phenotype ,Molecular biology ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,DNA methylation ,Metabolome - Abstract
Purpose: Mutations in Krebs cycle genes are frequently found in patients with pheochromocytomas/paragangliomas. Disruption of SDH, FH or MDH2 enzymatic activities lead to accumulation of specific metabolites, which give rise to epigenetic changes in the genome that cause a characteristic hypermethylated phenotype. Tumors showing this phenotype, but no alterations in the known predisposing genes, could harbor mutations in other Krebs cycle genes. Experimental Design: We used downregulation and methylation of RBP1, as a marker of a hypermethylation phenotype, to select eleven pheochromocytomas and paragangliomas for targeted exome sequencing of a panel of Krebs cycle-related genes. Methylation profiling, metabolite assessment and additional analyses were also performed in selected cases. Results: One of the 11 tumors was found to carry a known cancer-predisposing somatic mutation in IDH1. A variant in GOT2, c.357A>T, found in a patient with multiple tumors, was associated with higher tumor mRNA and protein expression levels, increased GOT2 enzymatic activity in lymphoblastic cells, and altered metabolite ratios both in tumors and in GOT2 knockdown HeLa cells transfected with the variant. Array methylation-based analysis uncovered a somatic epigenetic mutation in SDHC in a patient with multiple pheochromocytomas and a gastrointestinal stromal tumor. Finally, a truncating germline IDH3B mutation was found in a patient with a single paraganglioma showing an altered α-ketoglutarate/isocitrate ratio. Conclusions: This study further attests to the relevance of the Krebs cycle in the development of PCC and PGL, and points to a potential role of other metabolic enzymes involved in metabolite exchange between mitochondria and cytosol. Clin Cancer Res; 23(20); 6315–24. ©2017 AACR.
- Published
- 2016
14. CSF1R Protein Expression in Reactive Lymphoid Tissues and Lymphoma: Its Relevance in Classical Hodgkin Lymphoma
- Author
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Juan F. García, Jose Francisco Tomas, Ana M. Martín-Moreno, Jorge L. Martínez-Torrecuadrada, Carmen Rubio, Lorena Maestre, Karen Pulford, Giovanna Roncador, Miguel A. Piris, Scherezade Jiménez, Ana Isabel Reyes-García, Mónica Estévez, Elena Mata, Asociación Española Contra el Cáncer, Unión Europea, Ministerio de Ciencia e Innovación (España), Asociacion Espanola Contra el Cancer (AECC), European Union (EU), and Ministerio de Ciencia, Innovación (España)
- Subjects
Pathology ,medicine.medical_specialty ,PROGNOSIS ,Lymphoma ,Lymphoid Tissue ,FACTOR-I ,lcsh:Medicine ,Gene Expression ,PROGRESSION ,MICROENVIRONMENT ,Receptor, Macrophage Colony-Stimulating Factor ,macromolecular substances ,Biology ,medicine.disease_cause ,Mice ,BCL9 ,immune system diseases ,hemic and lymphatic diseases ,Cell Line, Tumor ,polycyclic compounds ,medicine ,Animals ,Humans ,Immunoprecipitation ,lcsh:Science ,REED-STERNBERG CELLS ,Anaplastic large-cell lymphoma ,Multidisciplinary ,CD68 ,lcsh:R ,food and beverages ,COLONY-STIMULATING FACTOR ,medicine.disease ,Epstein–Barr virus ,Hodgkin Disease ,Immunohistochemistry ,BCL10 ,TUMOR-ASSOCIATED MACROPHAGES ,Lymphatic system ,Cancer research ,SURVIVAL ,lcsh:Q ,INHIBITORS ,CD163 ,FOLLICULAR LYMPHOMA ,Research Article ,Signal Transduction - Abstract
Tumour-associated macrophages (TAMs) have been associated with survival in classic Hodgkin lymphoma (cHL) and other lymphoma types. The maturation and differentiation of tissue macrophages depends upon interactions between colony-stimulating factor 1 receptor (CSF1R) and its ligands. There remains, however, a lack of consistent information on CSF1R expression in TAMs. A new monoclonal antibody, FER216, was generated to investigate CSF1R protein distribution in formalin fixed tissue samples from 24 reactive lymphoid tissues and 187 different lymphoma types. We also analysed the distribution of CSF1R+, CD68+ and CD163+ macrophages by double immunostaining, and studied the relationship between CSF1R expression and survival in an independent series of 249 cHL patients. CSF1R+ TAMs were less frequent in B-cell lymphocytic leukaemia and lymphoblastic B-cell lymphoma than in diffuse large B-cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma and cHL. HRS cells in cHL and, with the exception of three cases of anaplastic large cell lymphoma, the neoplastic cells in NHLs, lacked detectable CSF1R protein. A CSF1R+ enriched microenvironment in cHL was associated with shorter survival in an independent series of 249 cHL patients. CSF1R pathway activation was evident in the cHL and inactivation of this pathway could be a potential therapeutic target in cHL cases. This work was supported by grants from the Fondo de Investigaciones Sanitarias - Ministerio de Ciencia e Innovacion (PI12/1832), and Spanish Cancer Research Networks-RTICC (RD12/0036/0060), cofunded by the Fondo Europeo de Desarrollo Regional (FEDER), and the Asociacion Espanola Contra el Cancer (AECC Scientific Foundation). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí
- Published
- 2015
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