85 results on '"Agirre X"'
Search Results
2. Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma
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Perez C., Botta C., Zabaleta A., Puig N., Cedena M. -T., Goicoechea I., Alameda D., Jose-Eneriz E. S., Merino J., Rodriguez-Otero P., Maia C., Alignani D., Maiso P., Manrique I., Lara-Astiaso D., Vilas-Zornoza A., Sarvide S., Riillo C., Rossi M., Rosinol L., Oriol A., Blanchard M. -J., Rios R., Sureda A., Martin J., Martinez R., Bargay J., de la Rubia J., Hernandez M. -T., Martinez-Lopez J., Orfao A., Agirre X., Prosper F., Mateos M. -V., Lahuerta J. -J., Blade J., San-Miguel J. F., Paiva B., Espinosa M. C., Zamudio J. L. G., Herranz E. R., Tamayo R. R., Sanchez J. M., Bernal L. P., Rodriguez A. P. G., Garcia M. E. G., Mayol A. S., Lleonart J. B., Suarez A., Garcia M. T. H., Gaisan C. M., Ruiz B. H., Montero F. C., de Miguel Llorente D., Ramos F. S., Garcia A. I., Manteca M. M., Martin J. M. H., Barrigon F. E., Frade J. G., de Coca A. G., Franco C. A., Gomez J. L., Perez E. C., Creixenti J. B., Balari A. M. S., Montes Y. G., Teigell L. E., Guinon A. G., Monreal E. A., Campos J. A. S., Tutusaus J. M. M., Rocafiguera A. O., Gorrochategui M. G., Mesa M. G., Silva C. C., Perez M. S. G., Loureiro A. D., Sanchez J. A. M., Irazu M. J. N., Parraga F. J. P., Palacios J. J. L., Barahona P. B., Rodriguez C. E., Rivas J. A. H., de Oteyza J. P., del Barrio R. I., de la Guia A. L., Amor A. A., Pareja E. P., Castello I. K., Rodriguez M. J. B., Martinez R. M., Grau R. R., Mesa E. G., Sainz E. R., de Arriba F., Jimenez J. M. M., Romera M., Cardoso F. P., Perez J. M. A., Pomposo M. P., Persona E. P., Casasus A. I. T., Garcia P. R., Ramos I. J., Lor M. B. V., Garcia P. L. F., Chamorro C. M., Perez C., Botta C., Zabaleta A., Puig N., Cedena M.-T., Goicoechea I., Alameda D., Jose-Eneriz E.S., Merino J., Rodriguez-Otero P., Maia C., Alignani D., Maiso P., Manrique I., Lara-Astiaso D., Vilas-Zornoza A., Sarvide S., Riillo C., Rossi M., Rosinol L., Oriol A., Blanchard M.-J., Rios R., Sureda A., Martin J., Martinez R., Bargay J., de la Rubia J., Hernandez M.-T., Martinez-Lopez J., Orfao A., Agirre X., Prosper F., Mateos M.-V., Lahuerta J.-J., Blade J., San-Miguel J.F., Paiva B., Espinosa M.C., Zamudio J.L.G., Herranz E.R., Tamayo R.R., Sanchez J.M., Bernal L.P., Rodriguez A.P.G., Garcia M.E.G., Mayol A.S., Lleonart J.B., Suarez A., Garcia M.T.H., Gaisan C.M., Ruiz B.H., Montero F.C., de Miguel Llorente D., Ramos F.S., Garcia A.I., Manteca M.M., Martin J.M.H., Barrigon F.E., Frade J.G., de Coca A.G., Franco C.A., Gomez J.L., Perez E.C., Creixenti J.B., Balari A.M.S., Montes Y.G., Teigell L.E., Guinon A.G., Monreal E.A., Campos J.A.S., Tutusaus J.M.M., Rocafiguera A.O., Gorrochategui M.G., Mesa M.G., Silva C.C., Perez M.S.G., Loureiro A.D., Sanchez J.A.M., Irazu M.J.N., Parraga F.J.P., Palacios J.J.L., Barahona P.B., Rodriguez C.E., Rivas J.A.H., de Oteyza J.P., del Barrio R.I., de la Guia A.L., Amor A.A., Pareja E.P., Castello I.K., Rodriguez M.J.B., Martinez R.M., Grau R.R., Mesa E.G., Sainz E.R., de Arriba F., Jimenez J.M.M., Romera M., Cardoso F.P., Perez J.M.A., Pomposo M.P., Persona E.P., Casasus A.I.T., Garcia P.R., Ramos I.J., Lor M.B.V., Garcia P.L.F., and Chamorro C.M.
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Male ,Transcription, Genetic ,Neutrophils ,T-Lymphocytes ,Immunology ,CD33 ,Biology ,CD16 ,Biochemistry ,Follow-Up Studie ,Flow cytometry ,Antigens, CD ,medicine ,Humans ,Cytotoxic T cell ,Lymphocyte Count ,Tumor microenvironment ,medicine.diagnostic_test ,Myeloid-Derived Suppressor Cells ,Cell Biology ,Hematology ,Middle Aged ,Cell sorting ,Neoplasm Proteins ,medicine.anatomical_structure ,T-Lymphocyte ,Cancer research ,Myeloid-derived Suppressor Cell ,Female ,Bone marrow ,Multiple Myeloma ,Human ,Follow-Up Studies - Abstract
Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14−CD15+CD33+HLADR− cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC–related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
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- 2020
3. Challenges in Charge Selection: Considerations informing the number of charges and cumulative charging practices
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Davis, C.J., Agirre, X., Bergsmo, M., De Smet, S., and Stahn, C.
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- 2020
4. Generation of a High Number of Healthy Erythroid Cells from Gene-Edited Pyruvate Kinase Deficiency Patient-Specific Induced Pluripotent Stem Cells
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Garate, Z, Quintana-Bustamante, O, Crane, AM, Olivier, E, Poirot, L, Galetto, R, Kosinski, P, Hill, C, Kung, C, Agirre, X, Orman, I, Cerrato, L, Alberquilla, O, Rodriguez-Fornes, F, Fusaki, N, Garcia-Sanchez, F, Maia, TM, Ribeiro, ML, Sevilla, J, Prosper, F, Jin, S, Mountford, J, Guenechea, G, Gouble, A, Bueren, JA, Davis, BR, and Segovia, JC
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Células Eritroides ,Recombination, Genetic ,Anemia Hemolítica Congénita não Esferocítica ,lcsh:R5-920 ,DNA, Complementary ,Base Sequence ,Induced Pluripotent Stem Cells ,Pyruvate Kinase ,Cell Count ,Anemia, Hemolytic, Congenital Nonspherocytic ,Genetic Therapy ,Pyruvate Metabolism, Inborn Errors ,Article ,Erythroid Cells ,lcsh:Biology (General) ,Gene Targeting ,Leukocytes, Mononuclear ,Piruvato Quinase ,Humans ,Erros Inatos do Metabolismo dos Piruvatos ,lcsh:Medicine (General) ,lcsh:QH301-705.5 ,Alleles ,Células-Tronco Pluripotentes Induzidas - Abstract
Summary Pyruvate kinase deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene. Erythrocytes from PKD patients show an energetic imbalance causing chronic non-spherocytic hemolytic anemia, as pyruvate kinase defects impair ATP production in erythrocytes. We generated PKD induced pluripotent stem cells (PKDiPSCs) from peripheral blood mononuclear cells (PB-MNCs) of PKD patients by non-integrative Sendai viral vectors. PKDiPSCs were gene edited to integrate a partial codon-optimized R-type pyruvate kinase cDNA in the second intron of the PKLR gene by TALEN-mediated homologous recombination (HR). Notably, we found allele specificity of HR led by the presence of a single-nucleotide polymorphism. High numbers of erythroid cells derived from gene-edited PKDiPSCs showed correction of the energetic imbalance, providing an approach to correct metabolic erythroid diseases and demonstrating the practicality of this approach to generate the large cell numbers required for comprehensive biochemical and metabolic erythroid analyses., Highlights • Patient-specific PKDiPSCs are generated from PB-MNCs by a non-integrative system • PKDiPSCs are gene edited to insert a partial co-RPK in the PKLR locus mediated by TALEN • An SNP in the homology arm leads to allele-specific homologous recombination • Gene-edited PKDiPSCs generate a high number of metabolically corrected erythroid cells, Patient-specific induced pluripotent stem cells (iPSCs) are the perfect platform to study erythroid metabolic diseases and test innovative treatments. Segovia, Quintana-Bustamante, and colleagues showed the correction of pyruvate kinase deficiency (PKD) by combining iPSC and gene-editing technologies and provide an approach to generate the large number of erythroid cells required for comprehensive biochemical and metabolic analyses of this disease and its treatment.
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- 2015
5. PF583 COMPREHENSIVE ANALYSIS OF THE COMPLEXITY AND HETEROGENEITY OF THE LNCRNAS TRANSCRIPTOME IN MULTIPLE MYELOMA
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Carrasco-Leon, A., primary, Ezponda, T., additional, Meydan, C., additional, Valcárcel, L.V., additional, Ordoñez, R., additional, Kulis, M., additional, Garate, L., additional, Miranda, E., additional, Segura, V., additional, Guruceaga, E., additional, Vilas-Zornoza, A., additional, Alignani, D., additional, Castro-Labrador, L., additional, Pascual, M., additional, Amundarain, A., additional, El-Omri, H., additional, Taha, R. Y, additional, Calasanz, M.J., additional, Planes, F.J., additional, Mason, C., additional, Miguel, J. San, additional, Subero, J.I. Martin, additional, Melnick, A., additional, Prosper, F., additional, and Agirre, X., additional
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- 2019
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6. S843 THE PROLIFERATIVE HISTORY SHAPES THE DNA METHYLOME OF B-CELL TUMORS AND PREDICTS CLINICAL OUTCOME
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Duran-Ferrer, M., primary, Clot, G., additional, Nadeu, F., additional, Beekman, R., additional, Baumann, T., additional, Nordlund, J., additional, Marincevic-Zuniga, Y., additional, Rivas-Delgado, A., additional, Ordoñez, R., additional, Castellano, G., additional, Kulis, M., additional, Queirós, A., additional, Seung-Tae, L., additional, Wiemels, J., additional, Royo, R., additional, Puiggrós, M., additional, Torrents, D., additional, Giné, E., additional, Beà, S., additional, Jares, P., additional, Agirre, X., additional, Prosper, F., additional, López-Otín, C., additional, Puente, X.S., additional, Delgado, J., additional, López-Guillermo, A., additional, Campo, E., additional, and Martín-Subero, J.I., additional
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- 2019
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7. PF567 CHROMATIN ACTIVATION AS A UNIFYING PRINCIPLE UNDERLYING PATHOGENIC MECHANISMS IN MULTIPLE MYELOMA
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Ordoñez, R., primary, Kulis, M., additional, Russiñol, N., additional, Chapaprieta, V., additional, Beekman, R., additional, Meydan, C., additional, Duran-Ferrer, M., additional, Verdaguer-Dot, N., additional, Clot, G., additional, Vilarrasa-Blasi, R., additional, Garate, L., additional, Miranda, E., additional, Carrasco, A., additional, Ezponda, T., additional, Martens, J.H.A., additional, El-Omri, H., additional, Taha, R.Y., additional, Calasanz, M.J., additional, Paiva, B., additional, Miguel, J. San, additional, Flicek, P., additional, Gut, I., additional, Melnick, A., additional, Mitsiades, C.S., additional, Licht, J.D., additional, Campo, E., additional, Stunnenberg, H.G., additional, Agirre, X., additional, Martin-Subero, J.I., additional, and Prósper, F., additional
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- 2019
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8. THE ANALYSIS OF EPIGENOE OF MULTIPE MYELOMA REVEALS A HYPERMETHYLATION OF THE DNA IN SPECIFIC ENHANCER REGIONS OF B CELLS
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Agirre, X., Castellano, G., Pascual, M., Heath, S., Kulis, M., Segura, V., Bergmann, A., Russinol, N., Queiros, A. C., Beekman, R., Rodriguez-Madoz Juan, R., San Jose-Eneriz, E., Gutierrez Norma, C., Garcia-Verdugo, J. M., Schirmer Eric, C., Gut, M., MJ Calasanz, Flicek, P., Siebert, R., Campo, E., San Miguel Jesus, F., Melnick, A., Stunnenberg Hendrik, G., Gut Ivo, G., Prosper, F., and Martin-Subero, J.
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GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Molecular Biology - Abstract
Contains fulltext : 150476.pdf (Publisher’s version ) (Open Access)
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- 2015
9. Use of human pharyngeal and palatine tonsils as a reservoir for the analysis of B-cell ontogeny in 10 paired samples
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Pascual, M., primary, Alignani, D., additional, Vilas-Zornoza, A., additional, Delgado, J.A., additional, Vázquez, I., additional, Malumbres, R., additional, Rodriguez, I., additional, Barriuso, R., additional, Calasanz, M.J., additional, Paiva, B., additional, Agirre, X., additional, Prósper, F., additional, and Cervera-Paz, F.J., additional
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- 2016
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10. Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers
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Agirre, X., primary, Castellano, G., additional, Pascual, M., additional, Heath, S., additional, Kulis, M., additional, Segura, V., additional, Bergmann, A., additional, Esteve, A., additional, Merkel, A., additional, Raineri, E., additional, Agueda, L., additional, Blanc, J., additional, Richardson, D., additional, Clarke, L., additional, Datta, A., additional, Russiñol, N., additional, Queirós, A.C., additional, Beekman, R., additional, Rodríguez-Madoz, J.R., additional, San José-Enériz, E., additional, Fang, F., additional, Gutiérrez, N.C., additional, García-Verdugo, J.M., additional, Robson, M.I., additional, Schirmer, E.C., additional, Guruceaga, E., additional, Martens, J.H.A., additional, Gut, M., additional, Calasanz, M.J., additional, Flicek, P., additional, Siebert, R., additional, Campo, E., additional, San Miguel, J.F., additional, Melnick, A., additional, Stunnenberg, H.G., additional, Gut, I.G., additional, Prosper, F., additional, and Martín-Subero, J.I., additional
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- 2015
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11. Upregulated expression and function of the α4β1 integrin in multiple myeloma cells resistant to bortezomib
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Anna Sánchez‐Vencells, Joaquin Martinez-Lopez, Mónica Martínez-Moreno, Antonio Valeri, Consuelo Gajate, Nohemí Arellano-Sánchez, Faustino Mollinedo, Xabier Agirre, Silvia Sevilla-Movilla, Luis Vitores Valcárcel, Felipe Prosper, Joaquin Teixidó, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Investigación Hospital 12 de Octubre, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Cáncer (España), Fundació La Marató de TV3, Diputación Foral de Navarra, Fundación Ramón Areces, Multiple Myeloma Research Foundation, International Myeloma Foundation, Qatar National Research Fund, Sevilla-Movilla, Silvia [0000-0002-4651-1813], Arellano-Sánchez, Nohemí [0000-0002-9309-6931], Martínez-Moreno, Mónica [0000-0002-1640-6297], Gajate, Consuelo [0000-0003-0604-6459], Sánchez‐Vencells, Anna [0000-0002-8992-4431], Vitores Valcárcel, Luis [0000-0003-3769-5419], Agirre, X. [0000-0002-6558-9560], Valeri, Antonio [0000-0002-7245-6977], Prosper, Felipe [0000-0001-6115-8790], Mollinedo, Faustino [0000-0002-4939-2434], Teixidó, Joaquín [0000-0002-3177-4151], Sevilla-Movilla, Silvia, Arellano-Sánchez, Nohemí, Martínez-Moreno, Mónica, Gajate, Consuelo, Sánchez‐Vencells, Anna, Vitores Valcárcel, Luis, Agirre, X., Valeri, Antonio, Prosper, Felipe, Mollinedo, Faustino, and Teixidó, Joaquín
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Integrins ,Integrin ,Cell ,Resistance ,Antineoplastic Agents ,Integrin alpha4beta1 ,Proteasome inhibitors ,Pathology and Forensic Medicine ,Bortezomib ,Mice ,Multiple myeloma ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Cell adhesion ,Cell Proliferation ,biology ,Cell growth ,Chemistry ,medicine.disease ,Prognosis ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Apoptosis ,Drug Resistance, Neoplasm ,biology.protein ,Cancer research ,Bone marrow ,Multiple Myeloma ,medicine.drug - Abstract
36 p.-6 fig., The interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes MM cell retention, survival and resistance to different anti‐MM agents, including proteasome inhibitors (PIs) such as bortezomib (BTZ). The α4β1 integrin is a main adhesion receptor mediating MM cell‐stroma interactions and MM cell survival, and its expression and function are downregulated by BTZ, leading to inhibition of cell adhesion‐mediated drug resistance (CAM‐DR) and MM cell apoptosis. Whether decreased α4β1 expression and activity is maintained or recovered upon development of resistance to BTZ represents an important question, as a potential rescue of α4β1 function could boost MM cell survival and disease progression. Using BTZ‐resistant MM cells, we found that they not only rescue their α4β1 expression, but its levels were higher than in parental cells. Increased α4β1 expression in resistant cells correlated with enhanced α4β1‐mediated cell lodging in the BM, and with disease progression. BTZ‐resistant MM cells displayed enhanced NF‐κB pathway activation relative to parental counterparts, which contributed to upregulated α4 expression and to α4β1‐dependent MM cell adhesion. These data emphasize the upregulation of α4β1 expression and function as a key event during resistance to BTZ in MM, which might indirectly contribute to stabilize this resistance, as stronger MM cell attachment to BM stroma will regain CAM‐DR and MM cell growth and survival. Finally, we found a strong correlation between high ITGB1 (integrin β1) expression in MM and poor progression‐free survival (PFS) and overall survival (OS) during treatment of MM patients with BTZ and IMIDs, and combination of high ITGB1 levels and presence of the high‐risk genetic factor amp1q causes low PFS and OS. These results unravel a novel prognostic value for ITGB1 in myeloma., This work was supported by grants SAF2014-53059-R and SAF2017-85146-R from the Ministerio de Ciencia, Innovación y Universidades (MCIU) to JT; SAF2017-89672-R from MCIU to FM; by the Research Institute Hospital 12 de Octubre (i+12) and grants from Instituto de Salud Carlos III (ISCIII) and CIBERONC to JML; by grants from ISCIII PI16/02024,PI17/00701 and PI19/01352, TRASCAN (EPICA and Immunocell), Fundació La Marató de TV3, the Accelerator award CRUK/AIRC/AECC joint funder-partnership, CIBERONC(CB16/12/00489) and co-financed with FEDER funds MINECO Explora (RTHALMY),Gobierno de Navarra, Departamento de Salud 40/2016 and Departamento de Industria (Proyecto Estrategico, Reto Genomica, DIANA) and Fundación Ramón Areces (PREMAMM) to FP and XA The study was also supported by the Multiple Myeloma Research Foundation Networks of excellence, the International Myeloma Foundation (Brian van Novis), and the Qatar National Research Fund award 7-916-3-237.
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- 2020
12. Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination
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Felipe Prosper, Luzalba Sanoja-Flores, Diego Alignani, Ibai Goicoechea, Juan José Garcés, Jesús F. San-Miguel, Patricia Maiso, Tereza Sevcikova, Sonia Garate, Leire Burgos, Pamela Millacoy, Halima El Omri, Roman Hájek, Alberto Orfao, Katerina Growkova, Alexander Vdovin, Bruno Paiva, Marco Vicari, Albert Pérez-Montaña, Xabier Agirre, Joaquin Martinez-Lopez, Rafael Rios, Luis Palomera, Renata Bezdekova, Marta Lasa, Juan Flores-Montero, Cirino Botta, Rafael Del Orbe, Tomas Jelinek, Michal Simicek, Zuzana Chyra, Lucie Brozova, Jonathan J Keats, Ludek Pour, Maria-Jose Calasanz, Laura Blanco, Instituto de Salud Carlos III, Cancer Research UK, Asociación Española Contra el Cáncer, Fundación Científica Asociación Española Contra el Cáncer, Fondazione Italiana per la Ricerca sul Cancro, International Myeloma Foundation, European Research Council, Czech Science Foundation, Ministry of Health of the Czech Republic, European Commission, Garces J.-J., Simicek M., Vicari M., Brozova L., Burgos L., Bezdekova R., Alignani D., Calasanz M.-J., Growkova K., Goicoechea I., Agirre X., Pour L., Prosper F., Rios R., Martinez-Lopez J., Millacoy P., Palomera L., Del Orbe R., Perez-Montana A., Garate S., Blanco L., Lasa M., Maiso P., Flores-Montero J., Sanoja-Flores L., Chyra Z., Vdovin A., Sevcikova T., Jelinek T., Botta C., El Omri H., Keats J., Orfao A., Hajek R., San-Miguel J.F., and Paiva B.
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0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Transcription, Genetic ,Gene Expression ,Biology ,circulating tumor cell ,03 medical and health sciences ,0302 clinical medicine ,Circulating tumor cell ,Bone Marrow ,Cell Movement ,Cancer stem cell ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Humans ,Hypoxia ,Multiple myeloma ,Cell Proliferation ,Inflammation ,Gene knockdown ,liquid biopsy ,CD44 ,CENPF ,Hematology ,Neoplastic Cells, Circulating ,Prognosis ,medicine.disease ,3. Good health ,multiple myeloma ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Cancer research ,biology.protein ,Bone marrow - Abstract
The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r ≥ 0.94, P = 10−16), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial–mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs. The cancer stem cell marker CD44 was overexpressed in CTCs, and its knockdown significantly reduced migration of MM cells towards SDF1-α and their adhesion to fibronectin. Approximately half (29/55) of genes differentially expressed in CTCs were prognostic in patients with newly-diagnosed myeloma (n = 553; CoMMpass). In a multivariate analysis including the R-ISS, overexpression of CENPF and LGALS1 was significantly associated with inferior survival. Altogether, these results help understanding the presence of CTCs in PB and suggest that hypoxic BM niches together with a pro-inflammatory microenvironment induce an arrest in proliferation, forcing tumor cells to circulate in PB and seek other BM niches to continue growing., This study was supported by the Centro de Investigación Biomédica en Red —Área de Oncología— del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369, CB16/12/00489, and CB16/12/00400), Cancer Research UK, FCAECC and AIRC under the Accelerator Award Programme, Instituto de Salud Carlos III and Asociación Española Contra el Cáncer by ERA-NET TRANSCAN-2 Programme (AC17/00101), the Black Swan Research Initiative of the International Myeloma Foundation, the European Research Council (ERC) 2015 Starting Grant (MYELOMANEXT, 680200), the Czech Science Foundation through Project No. 19-25354Y, the European Regional Development Fund—Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868), and the Ministry of Health of the Czech Republic (15-29667A).
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- 2020
13. Rna-loaded nanoparticles for the treatment of hematological cancers.
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Garbayo E, El Moukhtari SH, Rodríguez-Nogales C, Agirre X, Rodriguez-Madoz JR, Rodriguez-Marquez P, Prósper F, Couvreur P, and Blanco-Prieto MJ
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Hematological cancers encompass a diverse group of malignancies affecting the blood, bone marrow, lymph nodes, and spleen. These disorders present unique challenges due to their complex etiology and varied clinical manifestations. Despite significant advancements in understanding and treating hematological malignancies, innovative therapeutic approaches are continually sought to enhance patient outcomes. This review highlights the application of RNA nanoparticles (RNA-NPs) in the treatment of hematological cancers. We delve into detailed discussions on in vitro and preclinical studies involving RNA-NPs for adult patients, as well as the application of RNA-NPs in pediatric hematological cancer. The review also addresses ongoing clinical trials involving RNA-NPs and explores the emerging field of CAR-T therapy engineered by RNA-NPs. Finally, we discuss the challenges still faced in translating RNA-NP research to clinics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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14. Single-Nucleotide Polymorphisms in WNT Genes in Patients with Non-Syndromic Orofacial Clefts in a Polish Population.
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Zawiślak A, Woźniak K, Tartaglia G, Agirre X, Gupta S, Kawala B, Znamirowska-Bajowska A, Grocholewicz K, Prosper F, Lubiński J, and Jakubowska A
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Non-syndromic orofacial cleft (OFC) is the most common facial developmental defect in the global population. The etiology of these birth defects is complex and multifactorial, involving both genetic and environmental factors. This study aimed to determine if SNPs in the WNT gene family (rs1533767, rs708111, rs3809857, rs7207916, rs12452064) are associated with OFCs in a Polish population. The study included 627 individuals: 209 children with OFCs and 418 healthy controls. DNA was extracted from saliva for the study group and from umbilical cord blood for the control group. Polymorphism genotyping was conducted using quantitative PCR. No statistically significant association was found between four variants and clefts, with odds ratios for rs708111 being 1.13 (CC genotype) and 0.99 (CT genotype), for rs3809857 being 1.05 (GT genotype) and 0.95 (TT genotype), for rs7207916 being 0.86 (AA genotype) and 1.29 (AG genotype) and for rs12452064 being 0.97 (AA genotype) and 1.24 (AG genotype). However, the rs1533767 polymorphism in WNT showed a statistically significant increase in OFC risk for the GG genotype (OR = 1.76, p < 0.001). This research shows that the rs1533767 polymorphism in the WNT gene is an important risk marker for OFC in the Polish population.
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- 2024
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15. Epigenetic-based differentiation therapy for Acute Myeloid Leukemia.
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San José-Enériz E, Gimenez-Camino N, Rabal O, Garate L, Miranda E, Gómez-Echarte N, García F, Charalampopoulou S, Sáez E, Vilas-Zornoza A, San Martín-Uriz P, Valcárcel LV, Barrena N, Alignani D, Tamariz-Amador LE, Pérez-Ruiz A, Hilscher S, Schutkowski M, Alfonso-Pierola A, Martinez-Calle N, Larrayoz MJ, Paiva B, Calasanz MJ, Muñoz J, Isasa M, Martin-Subero JI, Pineda-Lucena A, Oyarzabal J, Agirre X, and Prósper F
- Subjects
- Humans, Cell Line, Tumor, Acetylation drug effects, Transcription Factors metabolism, Transcription Factors genetics, Gene Expression Regulation, Leukemic drug effects, Animals, Cell Differentiation drug effects, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism, Epigenesis, Genetic drug effects, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylase Inhibitors therapeutic use
- Abstract
Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer-promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia., (© 2024. The Author(s).)
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- 2024
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16. HDACi vorinostat protects muscle from degeneration after acute rotator cuff injury in mice.
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Gil-Melgosa L, Llombart-Blanco R, Extramiana L, Lacave I, Abizanda G, Miranda E, Agirre X, Prósper F, Pineda-Lucena A, Pons-Villanueva J, and Pérez-Ruiz A
- Abstract
Aims: Rotator cuff (RC) injuries are characterized by tendon rupture, muscle atrophy, retraction, and fatty infiltration, which increase injury severity and jeopardize adequate tendon repair. Epigenetic drugs, such as histone deacetylase inhibitors (HDACis), possess the capacity to redefine the molecular signature of cells, and they may have the potential to inhibit the transformation of the fibro-adipogenic progenitors (FAPs) within the skeletal muscle into adipocyte-like cells, concurrently enhancing the myogenic potential of the satellite cells., Methods: HDACis were added to FAPs and satellite cell cultures isolated from mice. The HDACi vorinostat was additionally administered into a RC injury animal model. Histological analysis was carried out on the isolated supra- and infraspinatus muscles to assess vorinostat anti-muscle degeneration potential., Results: Vorinostat, a HDACi compound, blocked the adipogenic transformation of muscle-associated FAPs in culture, promoting myogenic progression of the satellite cells. Furthermore, it protected muscle from degeneration after acute RC in mice in the earlier muscle degenerative stage after tenotomy., Conclusion: The HDACi vorinostat may be a candidate to prevent early muscular degeneration after RC injury., Competing Interests: The authors affirm that they do not possess any conflicting interests. A. Pérez-Ruiz reports that research support was provided by the Spanish Ministerio de Ciencia, Innovacion y Universidades (grant number PID2020-113822RB-C22) for this study. F. Prósper reports that the article processing charges were funded by the Foundation for Applied Medical Research., (© 2024 Gil-Melgosara et al.)
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- 2024
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17. An atlas of cells in the human tonsil.
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Massoni-Badosa R, Aguilar-Fernández S, Nieto JC, Soler-Vila P, Elosua-Bayes M, Marchese D, Kulis M, Vilas-Zornoza A, Bühler MM, Rashmi S, Alsinet C, Caratù G, Moutinho C, Ruiz S, Lorden P, Lunazzi G, Colomer D, Frigola G, Blevins W, Romero-Rivero L, Jiménez-Martínez V, Vidal A, Mateos-Jaimez J, Maiques-Diaz A, Ovejero S, Moreaux J, Palomino S, Gomez-Cabrero D, Agirre X, Weniger MA, King HW, Garner LC, Marini F, Cervera-Paz FJ, Baptista PM, Vilaseca I, Rosales C, Ruiz-Gaspà S, Talks B, Sidhpura K, Pascual-Reguant A, Hauser AE, Haniffa M, Prosper F, Küppers R, Gut IG, Campo E, Martin-Subero JI, and Heyn H
- Subjects
- Humans, Adult, Palatine Tonsil, B-Lymphocytes metabolism
- Abstract
Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas of the human tonsil composed of >556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well as spatial transcriptomics. This census identified 121 cell types and states, defined developmental trajectories, and enabled an understanding of the functional units of the tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer as locally active in follicle-associated T and B cells, and identified SIX5 as putative transcriptional regulator of plasma cell maturation. Analyses of a validation cohort confirmed the presence, annotation, and markers of tonsillar cell types and provided evidence of age-related compositional shifts. We demonstrate the value of this resource by annotating cells from B cell-derived mantle cell lymphomas, linking transcriptional heterogeneity to normal B cell differentiation states of the human tonsil., Competing Interests: Declaration of interests H.H. is co-founder of Omniscope, SAB member of Nanostring and MiRXES, and consultant to Moderna and Singularity. J.C.N. is consultant to Omniscope., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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18. Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer.
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Nunes SP, Morales L, Rubio C, Munera-Maravilla E, Lodewijk I, Suárez-Cabrera C, Martínez VG, Pérez-Escavy M, Pérez-Crespo M, Alonso Sánchez M, Montesinos E, San José-Enériz E, Agirre X, Prósper F, Pineda-Lucena A, Henrique R, Dueñas M, Correia MP, Jerónimo C, and Paramio JM
- Abstract
Alterations in the epigenetic machinery in both tumor and immune cells contribute to bladder cancer (BC) development, constituting a promising target as an alternative therapeutic option. Here, we have explored the effects of a novel histone deacetylase (HDAC) inhibitor CM-1758, alone or in combination with immune checkpoint inhibitors (ICI) in BC. We determined the antitumor effects of CM-1758 in various BC cell lines together with the induction of broad transcriptional changes, with focus on the epigenetic regulation of PD-L1. Using an immunocompetent syngeneic mouse model of metastatic BC, we studied the effects of CM-1758 alone or in combination with anti-PD-L1 not only on tumor cells, but also in the tumor microenvironment. In vitro, we found that CM-1758 has cytotoxic and cytostatic effects either by inducing apoptosis or cell cycle arrest in BC cells at low micromolar levels. PD-L1 is epigenetically regulated by histone acetylation marks and is induced after treatment with CM-1758. We also observed that treatment with CM-1758 led to an important delay in tumor growth and a higher CD8 + T cell tumor infiltration. Moreover, anti-PD-L1 alone or in combination with CM-1758 reprogramed macrophage differentiation towards a M1-like polarization state and increased of pro-inflammatory cytokines systemically, yielding potential further antitumor effects. Our results suggest the possibility of combining HDAC inhibitors with immunotherapies for the management of advanced metastatic BC., (© 2024. The Author(s).)
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- 2024
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19. Lipid nanoparticles for siRNA delivery in cancer treatment.
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El Moukhtari SH, Garbayo E, Amundarain A, Pascual-Gil S, Carrasco-León A, Prosper F, Agirre X, and Blanco-Prieto MJ
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- RNA, Small Interfering, Liposomes, Phospholipids, Nanoparticles chemistry, Neoplasms genetics, Neoplasms therapy
- Abstract
RNA-based therapies, and siRNAs in particular, have attractive therapeutic potential for cancer treatment due to their ability to silence genes that are imperative for tumor progression. To be effective and solve issues related to their poor half-life and poor pharmacokinetic properties, siRNAs require adequate drug delivery systems that protect them from degradation and allow intracellular delivery. Among the various delivery vehicles available, lipid nanoparticles have emerged as the leading choice. These nanoparticles consist of cholesterol, phospholipids, PEG-lipids and most importantly ionizable cationic lipids. These ionizable lipids enable the binding of negatively charged siRNA, resulting in the formation of stable and neutral lipid nanoparticles with exceptionally high encapsulation efficiency. Lipid nanoparticles have demonstrated their effectiveness and versatility in delivering not only siRNAs but also multiple RNA molecules, contributing to their remarkable success. Furthermore, the advancement of efficient manufacturing techniques such as microfluidics, enables the rapid mixing of two miscible solvents without the need for shear forces. This facilitates the reproducible production of lipid nanoparticles and holds enormous potential for scalability. This is shown by the increasing number of preclinical and clinical trials evaluating the potential use of siRNA-LNPs for the treatment of solid and hematological tumors as well as in cancer immunotherapy. In this review, we provide an overview of the progress made on siRNA-LNP development for cancer treatment and outline the current preclinical and clinical landscape in this area. Finally, the translational challenges required to bring siRNA-LNPs further into the clinic are also discussed., (Copyright © 2023. Published by Elsevier B.V.)
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- 2023
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20. Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.
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Larrayoz M, Garcia-Barchino MJ, Celay J, Etxebeste A, Jimenez M, Perez C, Ordoñez R, Cobaleda C, Botta C, Fresquet V, Roa S, Goicoechea I, Maia C, Lasaga M, Chesi M, Bergsagel PL, Larrayoz MJ, Calasanz MJ, Campos-Sanchez E, Martinez-Cano J, Panizo C, Rodriguez-Otero P, Vicent S, Roncador G, Gonzalez P, Takahashi S, Katz SG, Walensky LD, Ruppert SM, Lasater EA, Amann M, Lozano T, Llopiz D, Sarobe P, Lasarte JJ, Planell N, Gomez-Cabrero D, Kudryashova O, Kurilovich A, Revuelta MV, Cerchietti L, Agirre X, San Miguel J, Paiva B, Prosper F, and Martinez-Climent JA
- Subjects
- Mice, Animals, CD8-Positive T-Lymphocytes, Immune Evasion, T-Lymphocytes, Regulatory, Immunotherapy adverse effects, Tumor Microenvironment genetics, Multiple Myeloma therapy, Multiple Myeloma drug therapy
- Abstract
The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8
+ T cells with reduced immunosuppressive regulatory T (Treg ) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials., (© 2023. The Author(s).)- Published
- 2023
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21. RROL lncRNA role in multiple myeloma.
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Agirre X
- Subjects
- Humans, Chromatin, Cell Communication, RNA, Long Noncoding genetics, Multiple Myeloma genetics, Multiple Myeloma metabolism, MicroRNAs metabolism
- Published
- 2023
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22. Revealing cell populations catching the early stages of human embryo development in naive pluripotent stem cell cultures.
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Moya-Jódar M, Ullate-Agote A, Barlabé P, Rodríguez-Madoz JR, Abizanda G, Barreda C, Carvajal-Vergara X, Vilas-Zornoza A, Romero JP, Garate L, Agirre X, Coppiello G, Prósper F, and Aranguren XL
- Subjects
- Humans, Embryonic Development genetics, Endoderm, Germ Layers, Cell Differentiation genetics, Blastocyst, Embryo, Mammalian, Pluripotent Stem Cells
- Abstract
Naive human pluripotent stem cells (hPSCs) are defined as the in vitro counterpart of the human preimplantation embryo's epiblast and are used as a model system to study developmental processes. In this study, we report the discovery and characterization of distinct cell populations coexisting with epiblast-like cells in 5iLAF naive human induced PSC (hiPSC) cultures. It is noteworthy that these populations closely resemble different cell types of the human embryo at early developmental stages. While epiblast-like cells represent the main cell population, interestingly we detect a cell population with gene and transposable element expression profile closely resembling the totipotent eight-cell (8C)-stage human embryo, and three cell populations analogous to trophectoderm cells at different stages of their maturation process: transition, early, and mature stages. Moreover, we reveal the presence of cells resembling primitive endoderm. Thus, 5iLAF naive hiPSC cultures provide an excellent opportunity to model the earliest events of human embryogenesis, from the 8C stage to the peri-implantation period., Competing Interests: Conflict of interests J.P.R. is an employee and shareholder of 10x Genomics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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23. The transcriptomic landscape of elderly acute myeloid leukemia identifies B7H3 and BANP as a favorable signature in high-risk patients.
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Villar S, Ariceta B, Agirre X, Urribarri AD, Ayala R, Martínez-Cuadrón D, Bergua JM, Vives S, Algarra L, Tormo M, Martínez P, Serrano J, Simoes C, Herrera P, Calasanz MJ, Alfonso-Piérola A, Paiva B, Martínez-López J, San Miguel JF, Prósper F, and Montesinos P
- Abstract
Acute myeloid leukemia (AML) in the elderly remains a clinical challenge, with a five-year overall survival rate below 10%. The current ELN 2017 genetic risk classification considers cytogenetic and mutational characteristics to stratify fit AML patients into different prognostic groups. However, this classification is not validated for elderly patients treated with a non-intensive approach, and its performance may be suboptimal in this context. Indeed, the transcriptomic landscape of AML in the elderly has been less explored and it might help stratify this group of patients. In the current study, we analyzed the transcriptome of 224 AML patients > 65 years-old at diagnosis treated in the Spanish PETHEMA-FLUGAZA clinical trial in order to identify new prognostic biomarkers in this population. We identified a specific transcriptomic signature for high-risk patients with mutated TP53 or complex karyotype, revealing that low expression of B7H3 gene with high expression of BANP gene identifies a subset of high-risk AML patients surviving more than 12 months. This result was further validated in the BEAT AML cohort. This unique signature highlights the potential of transcriptomics to identify prognostic biomarkers in in elderly AML., Competing Interests: RA: Membership on an entity´s Board of Directors advisory committees: Incyte Corporation, Astellas; Honoraria: Novartis, Celgene and Incyte. MT: declares honoraria for lectures from Celgene, Pfizer, Novartis, Janssen, Merck Sharp & Dohme (MSD), Daiichi, and Servier SL, and membership on advisory boards with Celgene, Novartis, Roche, and Astellas. JS: declares honoraria for lectures, and membership on advisory boards with, Daiichi Sankyo, Pfizer, Celgene, Novartis, Roche, and Amgen. BP: served as a consultant for and received honoraria from Adaptive, Amgen, Becton Dickinson, Bristol Myers Squibb/Celgene, GSK, Janssen, Roche, Sanofi, and Takeda; and received research support from Bristol Myers Squibb/Celgene, GSK, Roche, Sanofi, and Takeda JM-L: declares honoraria for lectures from, and membership on advisory boards with, Janssen, BMS, Sanofi, Novartis, Incyte, Roche, and Amgen; and membership on the boards of directors of Hosea and Altum Sequencing. JFS-M: reports Consultancy, membership on an entity´s Board of Directors advisory committees: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda. FP: Honoraria and research funding: Oryzon, Janssen, BMS-Celgene. PM: declares Consultancy, membership on an entity´s Board of Directors advisory committees, research funding, speaker’s bureau: Celgene, Sanofi, Incyte, Karyopharm, Novartis, Stemline/Menarini, Agios, Astellas Pharma, Daiichi Sankyo; Membership on an entity´s Board of Directors advisory committees: Pfizer, Teva, AbbVie; Research Funding, Speakers Bureau: Janssen; Consultancy: Tolero Pharmaceutical, Forma Therapeutics, Glycomimetics. The remaining authors declare no competing financial interests., (Copyright © 2022 Villar, Ariceta, Agirre, Urribarri, Ayala, Martínez-Cuadrón, Bergua, Vives, Algarra, Tormo, Martínez, Serrano, Simoes, Herrera, Calasanz, Alfonso-Piérola, Paiva, Martínez-López, San Miguel, Prósper and Montesinos.)
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- 2022
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24. Aptamers, a New Therapeutic Opportunity for the Treatment of Multiple Myeloma.
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Amundarain A, Pastor F, Prósper F, and Agirre X
- Abstract
Multiple Myeloma (MM) remains an incurable disease due to high relapse rates and fast development of drug resistances. The introduction of monoclonal antibodies (mAb) has caused a paradigm shift in MM treatment, paving the way for targeted approaches with increased efficacy and reduced toxicities. Nevertheless, antibody-based therapies face several difficulties such as high immunogenicity, high production costs and limited conjugation capacity, which we believe could be overcome by the introduction of nucleic acid aptamers. Similar to antibodies, aptamers can bind to their targets with great affinity and specificity. However, their chemical nature reduces their immunogenicity and production costs, while it enables their conjugation to a wide variety of cargoes for their use as delivery agents. In this review, we summarize several aptamers that have been tested against MM specific targets with promising results, establishing the rationale for the further development of aptamer-based strategies against MM. In this direction, we believe that the study of novel plasma cell surface markers, the development of intracellular aptamers and further research on aptamers as building blocks for complex nanomedicines will lead to the generation of next-generation targeted approaches that will undoubtedly contribute to improve the management and life quality of MM patients.
- Published
- 2022
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25. NGS-Based Molecular Karyotyping of Multiple Myeloma: Results from the GEM12 Clinical Trial.
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Rosa-Rosa JM, Cuenca I, Medina A, Vázquez I, Sánchez-delaCruz A, Buenache N, Sánchez R, Jiménez C, Rosiñol L, Gutiérrez NC, Ruiz-Heredia Y, Barrio S, Oriol A, Martin-Ramos ML, Blanchard MJ, Ayala R, Ríos-Tamayo R, Sureda A, Hernández MT, de la Rubia J, Alkorta-Aranburu G, Agirre X, Bladé J, Mateos MV, Lahuerta JJ, San-Miguel JF, Calasanz MJ, Garcia-Sanz R, and Martínez-Lopez J
- Abstract
Next-generation sequencing (NGS) has greatly improved our ability to detect the genomic aberrations occurring in multiple myeloma (MM); however, its transfer to routine clinical labs and its validation in clinical trials remains to be established. We designed a capture-based NGS targeted panel to identify, in a single assay, known genetic alterations for the prognostic stratification of MM. The NGS panel was designed for the simultaneous study of single nucleotide and copy number variations, insertions and deletions, chromosomal translocations and V(D)J rearrangements. The panel was validated using a cohort of 149 MM patients enrolled in the GEM2012MENOS65 clinical trial. The results showed great global accuracy, with positive and negative predictive values close to 90% when compared with available data from fluorescence in situ hybridization and whole-exome sequencing. While the treatments used in the clinical trial showed high efficacy, patients defined as high-risk by the panel had shorter progression-free survival ( p = 0.0015). As expected, the mutational status of TP53 was significant in predicting patient outcomes ( p = 0.021). The NGS panel also efficiently detected clonal IGH rearrangements in 81% of patients. In conclusion, molecular karyotyping using a targeted NGS panel can identify relevant prognostic chromosomal abnormalities and translocations for the clinical management of MM patients.
- Published
- 2022
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26. Explainable artificial intelligence for precision medicine in acute myeloid leukemia.
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Gimeno M, San José-Enériz E, Villar S, Agirre X, Prosper F, Rubio A, and Carazo F
- Subjects
- Crizotinib therapeutic use, Humans, Precision Medicine methods, Artificial Intelligence, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology
- Abstract
Artificial intelligence (AI) can unveil novel personalized treatments based on drug screening and whole-exome sequencing experiments (WES). However, the concept of "black box" in AI limits the potential of this approach to be translated into the clinical practice. In contrast, explainable AI (XAI) focuses on making AI results understandable to humans. Here, we present a novel XAI method -called multi-dimensional module optimization (MOM)- that associates drug screening with genetic events, while guaranteeing that predictions are interpretable and robust. We applied MOM to an acute myeloid leukemia (AML) cohort of 319 ex-vivo tumor samples with 122 screened drugs and WES. MOM returned a therapeutic strategy based on the FLT3 , CBFβ-MYH11 , and NRAS status, which predicted AML patient response to Quizartinib, Trametinib, Selumetinib, and Crizotinib. We successfully validated the results in three different large-scale screening experiments. We believe that XAI will help healthcare providers and drug regulators better understand AI medical decisions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gimeno, San José-Enériz, Villar, Agirre, Prosper, Rubio and Carazo.)
- Published
- 2022
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27. Identifying Lethal Dependencies with HUGE Predictive Power.
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Gimeno M, San José-Enériz E, Rubio A, Garate L, Miranda E, Castilla C, Agirre X, Prosper F, and Carazo F
- Abstract
Recent functional genomic screens—such as CRISPR-Cas9 or RNAi screening—have fostered a new wave of targeted treatments based on the concept of synthetic lethality. These approaches identified LEthal Dependencies (LEDs) by estimating the effect of genetic events on cell viability. The multiple-hypothesis problem is related to a large number of gene knockouts limiting the statistical power of these studies. Here, we show that predictions of LEDs from functional screens can be dramatically improved by incorporating the “HUb effect in Genetic Essentiality” (HUGE) of gene alterations. We analyze three recent genome-wide loss-of-function screens—Project Score, CERES score and DEMETER score—identifying LEDs with 75 times larger statistical power than using state-of-the-art methods. Using acute myeloid leukemia, breast cancer, lung adenocarcinoma and colon adenocarcinoma as disease models, we validate that our predictions are enriched in a recent harmonized knowledge base of clinical interpretations of somatic genomic variants in cancer (AUROC > 0.87). Our approach is effective even in tumors with large genetic heterogeneity such as acute myeloid leukemia, where we identified LEDs not recalled by previous pipelines, including FLT3-mutant genotypes sensitive to FLT3 inhibitors. Interestingly, in-vitro validations confirm lethal dependencies of either NRAS or PTPN11 depending on the NRAS mutational status. HUGE will hopefully help discover novel genetic dependencies amenable for precision-targeted therapies in cancer. All the graphs showing lethal dependencies for the 19 tumor types analyzed can be visualized in an interactive tool.
- Published
- 2022
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28. G9a inhibition by CM-272: Developing a novel anti-tumoral strategy for castration-resistant prostate cancer using 2D and 3D in vitro models.
- Author
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Moreira-Silva F, Outeiro-Pinho G, Lobo J, Guimarães R, Gaspar VM, Mano JF, Agirre X, Pineda-Lucena A, Prosper F, Paramio JM, Henrique R, Correia MP, and Jerónimo C
- Subjects
- Cell Line, Tumor, Cell Proliferation, Cell Survival, Gene Expression Regulation, Neoplastic, Humans, Male, PC-3 Cells, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Castration-resistant prostate cancer (CRPC) is an incurable form of prostate cancer (PCa), with DNMT1 and G9a being reported as overexpressed, rendering them highly attractive targets for precision medicine. CM-272 is a dual inhibitor of both methyltransferases' activity. Herein, we assessed the response of different PCa cell lines to CM-272, in both 2D and 3D models, and explored the molecular mechanisms underlying CM-272 inhibitory effects. CRPC tissues displayed significantly higher DNMT1, G9a and H3K9me2 expression than localized PCa. In vitro, CM-272 caused a significant decrease in PCa cell viability and proliferation alongside with increased apoptotic levels. We disclose that, under the evaluated dose, CM-272 led to G9a activity inhibition, while not significantly affecting DNMT1 activity. Upon G9a knockdown, DU145 and PC3 showed decreased cell viability. Remarkably, DU145 cells treated with CM-272 or with G9a knockdown displayed no differences in viability, suggesting a SET-dependent mechanism. Contrarily, PC3 cell viability impact was higher in G9a knockdown, compared with CM-272 treatment, suggesting an additional G9a function. Moreover, DU145 cells overexpressing catalytically functional G9a disclosed higher resistance to CM-272 treatment, reinforcing that the drug mechanism of action is dependent on G9a catalytic function. Importantly, we successfully assembled spheroids from several prostate cell lines. Our results showed that CM-272 retained its anti-tumoral effects in 3D PCa models, leading to a clear reduction in cancer cell survival. We concluded that inhibition of G9a methyltransferase activity by CM-272 has anti-tumor effect in PCa cells, holding therapeutic potential against CRPC., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2022
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29. BOSO: A novel feature selection algorithm for linear regression with high-dimensional data.
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Valcárcel LV, San José-Enériz E, Cendoya X, Rubio Á, Agirre X, Prósper F, and Planes FJ
- Subjects
- Humans, Linear Models, Machine Learning, Algorithms, Neoplasms drug therapy, Neoplasms metabolism
- Abstract
With the frenetic growth of high-dimensional datasets in different biomedical domains, there is an urgent need to develop predictive methods able to deal with this complexity. Feature selection is a relevant strategy in machine learning to address this challenge. We introduce a novel feature selection algorithm for linear regression called BOSO (Bilevel Optimization Selector Operator). We conducted a benchmark of BOSO with key algorithms in the literature, finding a superior accuracy for feature selection in high-dimensional datasets. Proof-of-concept of BOSO for predicting drug sensitivity in cancer is presented. A detailed analysis is carried out for methotrexate, a well-studied drug targeting cancer metabolism., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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30. Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma.
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De Beck L, Awad RM, Basso V, Casares N, De Ridder K, De Vlaeminck Y, Gnata A, Goyvaerts C, Lecocq Q, San José-Enériz E, Verhulst S, Maes K, Vanderkerken K, Agirre X, Prosper F, Lasarte JJ, Mondino A, and Breckpot K
- Subjects
- Animals, DNA Methylation, Histones metabolism, Mice, Models, Theoretical, Vaccination, Melanoma, Experimental, Skin Neoplasms genetics, Skin Neoplasms therapy
- Abstract
Immunotherapy has improved the treatment of malignant skin cancer of the melanoma type, yet overall clinical response rates remain low. Combination therapies could be key to meet this cogent medical need. Because epigenetic hallmarks represent promising combination therapy targets, we studied the immunogenic potential of a dual inhibitor of histone methyltransferase G9a and DNA methyltransferases (DNMTs) in the preclinical B16-OVA melanoma model. Making use of tumor transcriptomic and functional analyses, methylation-targeted epigenetic reprogramming was shown to induce tumor cell cycle arrest and apoptosis in vitro coinciding with transient tumor growth delay and an IFN-I response in immune-competent mice. In consideration of a potential impact on immune cells, the drug was shown not to interfere with dendritic cell maturation or T-cell activation in vitro. Notably, the drug promoted dendritic cell and, to a lesser extent, T-cell infiltration in vivo, yet failed to sensitize tumor cells to programmed cell death-1 inhibition. Instead, it increased therapeutic efficacy of TCR-redirected T cell and dendritic cell vaccination, jointly increasing overall survival of B16-OVA tumor-bearing mice. The reported data confirm the prospect of methylation-targeted epigenetic reprogramming in melanoma and sustain dual G9a and DNMT inhibition as a strategy to tip the cancer-immune set-point towards responsiveness to active and adoptive vaccination against melanoma., Competing Interests: The dual G9a/DNMT inhibitor CM-272 pertains to patent WO2015192981A1, on which XA, FP, and ESJ-E are filed as inventors. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 De Beck, Awad, Basso, Casares, De Ridder, De Vlaeminck, Gnata, Goyvaerts, Lecocq, San José-Enériz, Verhulst, Maes, Vanderkerken, Agirre, Prosper, Lasarte, Mondino and Breckpot.)
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- 2022
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31. A network-based approach to integrate nutrient microenvironment in the prediction of synthetic lethality in cancer metabolism.
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Apaolaza I, San José-Enériz E, Valcarcel LV, Agirre X, Prosper F, and Planes FJ
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- Cell Line, Tumor, Genomics, Humans, Metabolic Networks and Pathways genetics, Nutrients, Tumor Microenvironment, Neoplasms genetics, Neoplasms metabolism, Synthetic Lethal Mutations genetics
- Abstract
Synthetic Lethality (SL) is currently defined as a type of genetic interaction in which the loss of function of either of two genes individually has limited effect in cell viability but inactivation of both genes simultaneously leads to cell death. Given the profound genomic aberrations acquired by tumor cells, which can be systematically identified with -omics data, SL is a promising concept in cancer research. In particular, SL has received much attention in the area of cancer metabolism, due to the fact that relevant functional alterations concentrate on key metabolic pathways that promote cellular proliferation. With the extensive prior knowledge about human metabolic networks, a number of computational methods have been developed to predict SL in cancer metabolism, including the genetic Minimal Cut Sets (gMCSs) approach. A major challenge in the application of SL approaches to cancer metabolism is to systematically integrate tumor microenvironment, given that genetic interactions and nutritional availability are interconnected to support proliferation. Here, we propose a more general definition of SL for cancer metabolism that combines genetic and environmental interactions, namely loss of gene functions and absence of nutrients in the environment. We extend our gMCSs approach to determine this new family of metabolic synthetic lethal interactions. A computational and experimental proof-of-concept is presented for predicting the lethality of dihydrofolate reductase (DHFR) inhibition in different environments. Finally, our approach is applied to identify extracellular nutrient dependences of tumor cells, elucidating cholesterol and myo-inositol depletion as potential vulnerabilities in different malignancies., Competing Interests: The authors declare no competing interests.
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- 2022
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32. Landscape and clinical significance of long noncoding RNAs involved in multiple myeloma expressed fusion transcripts.
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Amundarain A, Valcárcel LV, Ordoñez R, Garate L, Miranda E, Cendoya X, Carrasco-Leon A, Calasanz MJ, Paiva B, Meydan C, Mason CE, Melnick A, Rodriguez-Otero P, Martín-Subero JI, San Miguel J, Planes FJ, Prósper F, and Agirre X
- Subjects
- Female, Humans, Male, Gene Expression Regulation, Neoplastic, Multiple Myeloma genetics, Multiple Myeloma metabolism, RNA, Long Noncoding biosynthesis, RNA, Long Noncoding genetics, RNA, Neoplasm biosynthesis, RNA, Neoplasm genetics
- Published
- 2022
- Full Text
- View/download PDF
33. Insights into the mechanisms underlying aberrant SOX11 oncogene expression in mantle cell lymphoma.
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Vilarrasa-Blasi R, Verdaguer-Dot N, Belver L, Soler-Vila P, Beekman R, Chapaprieta V, Kulis M, Queirós AC, Parra M, Calasanz MJ, Agirre X, Prosper F, Beà S, Colomer D, Marti-Renom MA, Ferrando A, Campo E, and Martin-Subero JI
- Subjects
- Humans, Lymphoma, Mantle-Cell genetics, Tumor Cells, Cultured, Chromatin Assembly and Disassembly, Enhancer Elements, Genetic, Lymphoma, Mantle-Cell pathology, Promoter Regions, Genetic, SOXC Transcription Factors genetics
- Published
- 2022
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34. Cereblon enhancer methylation and IMiD resistance in multiple myeloma.
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Haertle L, Barrio S, Munawar U, Han S, Zhou X, Vogt C, Fernández RA, Bittrich M, Ruiz-Heredia Y, Da Viá M, Zovko J, Garitano-Trojaola A, Bolli N, Ruckdeschel A, Stühmer T, Chatterjee M, Kull M, Krönke J, Agirre X, Martin-Subero JI, Raab P, Einsele H, Rasche L, Martinez-Lopez J, Haaf T, and Kortüm KM
- Subjects
- DNA Methylation drug effects, Drug Resistance, Neoplasm, Enhancer Elements, Genetic drug effects, Humans, Introns drug effects, Multiple Myeloma genetics, Adaptor Proteins, Signal Transducing genetics, Antineoplastic Agents, Immunological therapeutic use, Immunomodulating Agents therapeutic use, Multiple Myeloma drug therapy, Ubiquitin-Protein Ligases genetics
- Abstract
Cereblon is the direct binding target of the immunomodulatory drugs (IMiDs) that are commonly used to treat multiple myeloma (MM), the second most frequent hematologic malignancy. Patients respond well to initial treatment with IMiDs, but virtually all patients develop drug resistance over time, and the underlying mechanisms are poorly understood. We identified an as yet undescribed DNA hypermethylation in an active intronic CRBN enhancer. Differential hypermethylation in this region was found to be increased in healthy plasma cells, but was more pronounced in IMiD-refractory MM. Methylation significantly correlated with decreased CRBN expression levels. DNA methyltransferase inhibitor (DNTMi) in vitro experiments induced CRBN enhancer demethylation, and sensitizing effects on lenalidomide treatment were observed in 2 MM cell lines. Thus, we provide first evidence that aberrant CRBN DNA methylation is a novel mechanism of IMiD resistance in MM and may predict IMiD response prior to treatment., (© 2021 by The American Society of Hematology.)
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- 2021
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35. Association of ABCA4 Gene Polymorphisms with Cleft Lip with or without Cleft Palate in the Polish Population.
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Zawiślak A, Woźniak K, Agirre X, Gupta S, Kawala B, Znamirowska-Bajowska A, Grocholewicz K, Lubiński J, Prosper F, and Jakubowska A
- Subjects
- ATP-Binding Cassette Transporters genetics, Case-Control Studies, Child, Genetic Predisposition to Disease, Genotype, Humans, Poland epidemiology, Polymorphism, Single Nucleotide, Cleft Lip epidemiology, Cleft Lip genetics, Cleft Palate epidemiology, Cleft Palate genetics
- Abstract
Background: Non-syndromic cleft lip with/without cleft palate (NSCL/P) is a common congenital condition with a complex aetiology reflecting multiple genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in ABCA4 have been associated with NSCL/P in several studies, although there are some inconsistent results. This study aimed to evaluate whether two SNPs in ABCA4 , namely rs4147811 and rs560426, are associated with NSCL/P occurrence in the Polish population., Methods: The study included 627 participants: 209 paediatric patients with NSCL/P and 418 healthy newborn controls. DNA was isolated from the saliva of NSCL/P patients and from umbilical cord blood in the controls. Genotyping of rs4147811 and rs560426 was performed using quantitative PCR., Results: The rs4147811 (AG genotype) SNP in ABCA4 was associated with a decreased risk of NSCL/P (odds ratio (OR) 0.57; 95% confidence interval (CI) 0.39-0.84; p = 0.004), whereas the rs560426 (GG genotype) SNP was associated with an increased risk of NSCL/P (OR 2.13; 95% CI 1.31-3.48; p = 0.002)., Limitations: This study-based on the correlation between single genetic variants and the occurrence of different phenotypes-might have limited power in detecting relevant, complex inheritance patterns. ORs are often low to moderate when investigating the association of single genes with the risk of a complex trait. Another limitation was the small number of available NSCL/P samples., Conclusions: The results suggest that genetic variations in ABCA4 are important risk markers of NSCL/P in the Polish population. Further investigation in a larger study group is warranted.
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- 2021
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36. Gene expression derived from alternative promoters improves prognostic stratification in multiple myeloma.
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Valcárcel LV, Amundarain A, Kulis M, Charalampopoulou S, Melnick A, San Miguel J, Martín-Subero JI, Planes FJ, Agirre X, and Prosper F
- Subjects
- Gene Expression Profiling, Humans, Multiple Myeloma classification, Multiple Myeloma genetics, Prognosis, Survival Rate, Biomarkers, Tumor genetics, Gene Expression Regulation, Neoplastic, Multiple Myeloma pathology, Promoter Regions, Genetic, Transcriptome
- Abstract
Clinical and genetic risk factors are currently used in multiple myeloma (MM) to stratify patients and to design specific therapies. However, these systems do not capture the heterogeneity of the disease supporting the development of new prognostic factors. In this study, we identified active promoters and alternative active promoters in 6 different B cell subpopulations, including bone-marrow plasma cells, and 32 MM patient samples, using RNA-seq data. We find that expression initiated at both regular and alternative promoters was specific of each B cell subpopulation or MM plasma cells, showing a remarkable level of consistency with chromatin-based promoter definition. Interestingly, using 595 MM patient samples from the CoMMpass dataset, we observed that the expression derived from some alternative promoters was associated with lower progression-free and overall survival in MM patients independently of genetic alterations. Altogether, our results define cancer-specific alternative active promoters as new transcriptomic features that can provide a new avenue for prognostic stratification possibilities in patients with MM., (© 2021. The Author(s).)
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- 2021
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37. Endogenous Retroelement Activation by Epigenetic Therapy Reverses the Warburg Effect and Elicits Mitochondrial-Mediated Cancer Cell Death.
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Fresquet V, Garcia-Barchino MJ, Larrayoz M, Celay J, Vicente C, Fernandez-Galilea M, Larrayoz MJ, Calasanz MJ, Panizo C, Junza A, Han J, Prior C, Fortes P, Pio R, Oyarzabal J, Martinez-Baztan A, Paiva B, Moreno-Aliaga MJ, Odero MD, Agirre X, Yanes O, Prosper F, and Martinez-Climent JA
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Humans, Antineoplastic Agents pharmacology, Epigenesis, Genetic drug effects, Mitochondria drug effects, Neoplasms drug therapy
- Abstract
For millions of years, endogenous retroelements have remained transcriptionally silent within mammalian genomes by epigenetic mechanisms. Modern anticancer therapies targeting the epigenetic machinery awaken retroelement expression, inducing antiviral responses that eliminate tumors through mechanisms not completely understood. Here, we find that massive binding of epigenetically activated retroelements by RIG-I and MDA5 viral sensors promotes ATP hydrolysis and depletes intracellular energy, driving tumor killing independently of immune signaling. Energy depletion boosts compensatory ATP production by switching glycolysis to mitochondrial oxidative phosphorylation, thereby reversing the Warburg effect. However, hyperfunctional succinate dehydrogenase in mitochondrial electron transport chain generates excessive oxidative stress that unleashes RIP1-mediated necroptosis. To maintain ATP generation, hyperactive mitochondrial membrane blocks intrinsic apoptosis by increasing BCL2 dependency. Accordingly, drugs targeting BCL2 family proteins and epigenetic inhibitors yield synergistic responses in multiple cancer types. Thus, epigenetic therapy kills cancer cells by rewiring mitochondrial metabolism upon retroelement activation, which primes mitochondria to apoptosis by BH3-mimetics. SIGNIFICANCE: The state of viral mimicry induced by epigenetic therapies in cancer cells remodels mitochondrial metabolism and drives caspase-independent tumor cell death, which sensitizes to BCL2 inhibitor drugs. This novel mechanism underlies clinical efficacy of hypomethylating agents and venetoclax in acute myeloid leukemia, suggesting similar combination therapies for other incurable cancers. This article is highlighted in the In This Issue feature, p. 995 ., (©2020 American Association for Cancer Research.)
- Published
- 2021
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38. Characterization of complete lncRNAs transcriptome reveals the functional and clinical impact of lncRNAs in multiple myeloma.
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Carrasco-Leon A, Ezponda T, Meydan C, Valcárcel LV, Ordoñez R, Kulis M, Garate L, Miranda E, Segura V, Guruceaga E, Vilas-Zornoza A, Alignani D, Pascual M, Amundarain A, Castro-Labrador L, Martín-Uriz PS, El-Omri H, Taha RY, Calasanz MJ, Planes FJ, Paiva B, Mason CE, San Miguel JF, Martin-Subero JI, Melnick A, Prosper F, and Agirre X
- Subjects
- Apoptosis genetics, Cell Proliferation genetics, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic genetics, Humans, Progression-Free Survival, Multiple Myeloma genetics, RNA, Long Noncoding genetics, Transcriptome genetics
- Abstract
Multiple myeloma (MM) is an incurable disease, whose clinical heterogeneity makes its management challenging, highlighting the need for biological features to guide improved therapies. Deregulation of specific long non-coding RNAs (lncRNAs) has been shown in MM, nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we identified 40,511 novel lncRNAs in MM samples. lncRNAs accounted for 82% of the MM transcriptome and were more heterogeneously expressed than coding genes. A total of 10,351 overexpressed and 9,535 downregulated lncRNAs were identified in MM patients when compared with normal bone-marrow plasma cells. Transcriptional dynamics study of lncRNAs in the context of normal B-cell maturation revealed 989 lncRNAs with exclusive expression in MM, among which 89 showed de novo epigenomic activation. Knockdown studies on one of these lncRNAs, SMILO (specific myeloma intergenic long non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. We also showed that the expression of lncRNAs, together with clinical and genetic risk alterations, stratified MM patients into several progression-free survival and overall survival groups. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease.
- Published
- 2021
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39. The Role of lncRNAs in the Pathobiology and Clinical Behavior of Multiple Myeloma.
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Carrasco-León A, Amundarain A, Gómez-Echarte N, Prósper F, and Agirre X
- Abstract
MM is a hematological neoplasm that is still considered an incurable disease. Besides established genetic alterations, recent studies have shown that MM pathogenesis is also characterized by epigenetic aberrations, such as the gain of de novo active chromatin marks in promoter and enhancer regions and extensive DNA hypomethylation of intergenic regions, highlighting the relevance of these non-coding genomic regions. A recent study described how long non-coding RNAs (lncRNAs) correspond to 82% of the MM transcriptome and an increasing number of studies have demonstrated the importance of deregulation of lncRNAs in MM. In this review we focus on the deregulated lncRNAs in MM, including their biological or functional mechanisms, their role as biomarkers to improve the prognosis and monitoring of MM patients, and their participation in drug resistance. Furthermore, we also discuss the evidence supporting the role of lncRNAs as therapeutic targets through different novel RNA-based strategies.
- Published
- 2021
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40. Epigenetic Modifiers: Anti-Neoplastic Drugs With Immunomodulating Potential.
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Maes K, Mondino A, Lasarte JJ, Agirre X, Vanderkerken K, Prosper F, and Breckpot K
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy methods, DNA Methylation drug effects, DNA Methylation immunology, Drug Synergism, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Epigenesis, Genetic immunology, Gene Expression Regulation, Neoplastic immunology, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Immunotherapy, Adoptive methods, Neoplasms genetics, Neoplasms immunology, Protein Processing, Post-Translational drug effects, Protein Processing, Post-Translational immunology, Receptors, Chimeric Antigen immunology, Treatment Outcome, Tumor Escape genetics, Tumor Microenvironment drug effects, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Epigenesis, Genetic drug effects, Gene Expression Regulation, Neoplastic drug effects, Neoplasms therapy, Tumor Escape drug effects
- Abstract
Cancer cells are under the surveillance of the host immune system. Nevertheless, a number of immunosuppressive mechanisms allow tumors to escape protective responses and impose immune tolerance. Epigenetic alterations are central to cancer cell biology and cancer immune evasion. Accordingly, epigenetic modulating agents (EMAs) are being exploited as anti-neoplastic and immunomodulatory agents to restore immunological fitness. By simultaneously acting on cancer cells, e.g. by changing expression of tumor antigens, immune checkpoints, chemokines or innate defense pathways, and on immune cells, e.g. by remodeling the tumor stroma or enhancing effector cell functionality, EMAs can indeed overcome peripheral tolerance to transformed cells. Therefore, combinations of EMAs with chemo- or immunotherapy have become interesting strategies to fight cancer. Here we review several examples of epigenetic changes critical for immune cell functions and tumor-immune evasion and of the use of EMAs in promoting anti-tumor immunity. Finally, we provide our perspective on how EMAs could represent a game changer for combinatorial therapies and the clinical management of cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Maes, Mondino, Lasarte, Agirre, Vanderkerken, Prosper and Breckpot.)
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- 2021
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41. Design and Synthesis of Novel Epigenetic Inhibitors Targeting Histone Deacetylases, DNA Methyltransferase 1, and Lysine Methyltransferase G9a with In Vivo Efficacy in Multiple Myeloma.
- Author
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Rabal O, San José-Enériz E, Agirre X, Sánchez-Arias JA, de Miguel I, Ordoñez R, Garate L, Miranda E, Sáez E, Vilas-Zornoza A, Pineda-Lucena A, Estella A, Zhang F, Wu W, Xu M, Prosper F, and Oyarzabal J
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Proliferation drug effects, DNA (Cytosine-5-)-Methyltransferase 1 metabolism, Drug Design, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Histocompatibility Antigens metabolism, Histone Deacetylase Inhibitors therapeutic use, Histone Deacetylases metabolism, Histone-Lysine N-Methyltransferase metabolism, Humans, Mice, Inbred BALB C, Molecular Docking Simulation, Neoplasms drug therapy, Neoplasms metabolism, Mice, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, DNA (Cytosine-5-)-Methyltransferase 1 antagonists & inhibitors, Histone Deacetylase Inhibitors chemistry, Histone Deacetylase Inhibitors pharmacology, Histone-Lysine N-Methyltransferase antagonists & inhibitors
- Abstract
Concomitant inhibition of key epigenetic pathways involved in silencing tumor suppressor genes has been recognized as a promising strategy for cancer therapy. Herein, we report a first-in-class series of quinoline-based analogues that simultaneously inhibit histone deacetylases (from a low nanomolar range) and DNA methyltransferase-1 (from a mid-nanomolar range, IC
50 < 200 nM). Additionally, lysine methyltransferase G9a inhibitory activity is achieved (from a low nanomolar range) by introduction of a key lysine mimic group at the 7-position of the quinoline ring. The corresponding epigenetic functional cellular responses are observed: histone-3 acetylation, DNA hypomethylation, and decreased histone-3 methylation at lysine-9. These chemical probes, multitarget epigenetic inhibitors, were validated against the multiple myeloma cell line MM1.S, demonstrating promising in vitro activity of 12a (CM-444) with GI50 of 32 nM, an adequate therapeutic window (>1 log unit), and a suitable pharmacokinetic profile. In vivo , 12a achieved significant antitumor efficacy in a xenograft mouse model of human multiple myeloma.- Published
- 2021
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42. Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation.
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Vilarrasa-Blasi R, Soler-Vila P, Verdaguer-Dot N, Russiñol N, Di Stefano M, Chapaprieta V, Clot G, Farabella I, Cuscó P, Kulis M, Agirre X, Prosper F, Beekman R, Beà S, Colomer D, Stunnenberg HG, Gut I, Campo E, Marti-Renom MA, and Martin-Subero JI
- Subjects
- B-Lymphocytes cytology, Gene Expression Regulation, Neoplastic, Genomics methods, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell pathology, B-Lymphocytes metabolism, Cell Differentiation genetics, Cell Transformation, Neoplastic genetics, Chromatin genetics, Chromatin Assembly and Disassembly genetics, Genome, Human genetics
- Abstract
To investigate the three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia and mantle cell lymphoma patients, here we integrate in situ Hi-C and nine additional omics layers. Beyond conventional active (A) and inactive (B) compartments, we uncover a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, 28% of the compartments change, mostly involving a widespread chromatin activation from naive to germinal center B cells and a reversal to the naive state upon further maturation into memory B cells. B cell neoplasms are characterized by both entity and subtype-specific alterations in 3D genome organization, including large chromatin blocks spanning key disease-specific genes. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.
- Published
- 2021
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43. Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease.
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Garcia-Gomez A, Li T, de la Calle-Fabregat C, Rodríguez-Ubreva J, Ciudad L, Català-Moll F, Godoy-Tena G, Martín-Sánchez M, San-Segundo L, Muntión S, Morales X, Ortiz-de-Solórzano C, Oyarzabal J, San José-Enériz E, Esteller M, Agirre X, Prosper F, Garayoa M, and Ballestar E
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents therapeutic use, Bone Diseases diagnosis, Bone Diseases genetics, Bone Diseases pathology, Bone Marrow pathology, DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors, DNA (Cytosine-5-)-Methyltransferases metabolism, Enzyme Inhibitors therapeutic use, Epigenesis, Genetic drug effects, Female, Femur diagnostic imaging, Femur pathology, Gene Expression Regulation, Neoplastic drug effects, Histocompatibility Antigens metabolism, Histone-Lysine N-Methyltransferase antagonists & inhibitors, Histone-Lysine N-Methyltransferase metabolism, Humans, Male, Mesenchymal Stem Cells pathology, Mice, Middle Aged, Multiple Myeloma complications, Multiple Myeloma genetics, Multiple Myeloma pathology, Osteogenesis drug effects, Osteogenesis genetics, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Bone Diseases drug therapy, DNA Methylation drug effects, Enzyme Inhibitors pharmacology, Mesenchymal Stem Cells drug effects, Multiple Myeloma drug therapy
- Abstract
Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs). MM-MSCs exhibit abnormal transcriptomes, suggesting the involvement of epigenetic mechanisms governing their tumor-promoting functions and prolonged osteoblast suppression. Here, we identify widespread DNA methylation alterations of bone marrow-isolated MSCs from distinct MM stages, particularly in Homeobox genes involved in osteogenic differentiation that associate with their aberrant expression. Moreover, these DNA methylation changes are recapitulated in vitro by exposing MSCs from healthy individuals to MM cells. Pharmacological targeting of DNMTs and G9a with dual inhibitor CM-272 reverts the expression of hypermethylated osteogenic regulators and promotes osteoblast differentiation of myeloma MSCs. Most importantly, CM-272 treatment prevents tumor-associated bone loss and reduces tumor burden in a murine myeloma model. Our results demonstrate that epigenetic aberrancies mediate the impairment of bone formation in MM, and its targeting by CM-272 is able to reverse MBD.
- Published
- 2021
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44. Circulating tumor cells for comprehensive and multiregional non-invasive genetic characterization of multiple myeloma.
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Garcés JJ, Bretones G, Burgos L, Valdes-Mas R, Puig N, Cedena MT, Alignani D, Rodriguez I, Puente DÁ, Álvarez MG, Goicoechea I, Rodriguez S, Calasanz MJ, Agirre X, Flores-Montero J, Sanoja-Flores L, Rodriguez-Otero P, Rios R, Martinez-Lopez J, Millacoy P, Palomera L, Del Orbe R, Pérez-Montaña A, El Omri H, Prosper F, Mateos MV, Rosiñol L, Blade J, Lahuerta JJ, Orfao A, Lopez-Otin C, San Miguel JF, and Paiva B
- Subjects
- Computational Biology methods, DNA Copy Number Variations, DNA Mutational Analysis, Female, Genetic Heterogeneity, Humans, Immunophenotyping, Liquid Biopsy, Male, Mutation, Neoplasm Staging, Prognosis, Recurrence, Whole Genome Sequencing, Biomarkers, Tumor, Multiple Myeloma diagnosis, Multiple Myeloma genetics, Neoplastic Cells, Circulating metabolism, Neoplastic Cells, Circulating pathology
- Abstract
Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood (PB) of virtually all MM cases and are prognostic, but their applicability for noninvasive screening has been poorly investigated. Here, we used next-generation flow (NGF) cytometry to isolate matched CTCs and BM tumor cells from 53 patients and compared their genetic profile. In eight cases, tumor cells from extramedullary (EM) plasmacytomas were also sorted and whole-exome sequencing was performed in the three spatially distributed tumor samples. CTCs were detectable by NGF in the PB of all patients with MM. Based on the cancer cell fraction of clonal and subclonal mutations, we found that ~22% of CTCs egressed from a BM (or EM) site distant from the matched BM aspirate. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy number alterations (≥95%) though not for translocations (39%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Noteworthy, ≥82% mutations present in BM and EM clones were detectable in CTCs. Altogether, these results support CTCs for noninvasive risk-stratification of MM patients based on their numbers and genetic profile.
- Published
- 2020
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45. The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome.
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Duran-Ferrer M, Clot G, Nadeu F, Beekman R, Baumann T, Nordlund J, Marincevic-Zuniga Y, Lönnerholm G, Rivas-Delgado A, Martín S, Ordoñez R, Castellano G, Kulis M, Queirós AC, Lee ST, Wiemels J, Royo R, Puiggrós M, Lu J, Giné E, Beà S, Jares P, Agirre X, Prosper F, López-Otín C, Puente XS, Oakes CC, Zenz T, Delgado J, López-Guillermo A, Campo E, and Martín-Subero JI
- Subjects
- DNA Methylation genetics, Epigenesis, Genetic genetics, Gene Expression Regulation, Neoplastic, Humans, Epigenome genetics, Neoplasms
- Abstract
We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive patient-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. Subsequently, we construct a DNA methylation-based mitotic clock called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in the differential diagnosis and prediction of clinical outcome., Competing Interests: COMPETING INTERESTS The authors declare no competing interests.
- Published
- 2020
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46. Upregulated expression and function of the α4β1 integrin in multiple myeloma cells resistant to bortezomib.
- Author
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Sevilla-Movilla S, Arellano-Sánchez N, Martínez-Moreno M, Gajate C, Sánchez-Vencells A, Valcárcel LV, Agirre X, Valeri A, Martínez-López J, Prósper F, Mollinedo F, and Teixidó J
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation drug effects, Humans, Integrin alpha4beta1 genetics, Mice, Multiple Myeloma genetics, Multiple Myeloma pathology, Tumor Microenvironment, Antineoplastic Agents administration & dosage, Bortezomib administration & dosage, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Integrin alpha4beta1 metabolism, Multiple Myeloma metabolism
- Abstract
The interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes MM cell retention, survival, and resistance to different anti-MM agents, including proteasome inhibitors (PIs) such as bortezomib (BTZ). The α4β1 integrin is a main adhesion receptor mediating MM cell-stroma interactions and MM cell survival, and its expression and function are downregulated by BTZ, leading to inhibition of cell adhesion-mediated drug resistance (CAM-DR) and MM cell apoptosis. Whether decreased α4β1 expression and activity are maintained or recovered upon development of resistance to BTZ represents an important question, as a potential rescue of α4β1 function could boost MM cell survival and disease progression. Using BTZ-resistant MM cells, we found that they not only rescue their α4β1 expression, but its levels were higher than in parental cells. Increased α4β1 expression in resistant cells correlated with enhanced α4β1-mediated cell lodging in the BM, and with disease progression. BTZ-resistant MM cells displayed enhanced NF-κB pathway activation relative to parental counterparts, which contributed to upregulated α4 expression and to α4β1-dependent MM cell adhesion. These data emphasize the upregulation of α4β1 expression and function as a key event during resistance to BTZ in MM, which might indirectly contribute to stabilize this resistance, as stronger MM cell attachment to BM stroma will regain CAM-DR and MM cell growth and survival. Finally, we found a strong correlation between high ITGB1 (integrin β1) expression in MM and poor progression-free survival (PFS) and overall survival (OS) during treatment of MM patients with BTZ and IMIDs, and combination of high ITGB1 levels and presence of the high-risk genetic factor amp1q causes low PFS and OS. These results unravel a novel prognostic value for ITGB1 in myeloma. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2020
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47. Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma.
- Author
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Ordoñez R, Kulis M, Russiñol N, Chapaprieta V, Carrasco-Leon A, García-Torre B, Charalampopoulou S, Clot G, Beekman R, Meydan C, Duran-Ferrer M, Verdaguer-Dot N, Vilarrasa-Blasi R, Soler-Vila P, Garate L, Miranda E, San José-Enériz E, Rodriguez-Madoz JR, Ezponda T, Martínez-Turrilas R, Vilas-Zornoza A, Lara-Astiaso D, Dupéré-Richer D, Martens JHA, El-Omri H, Taha RY, Calasanz MJ, Paiva B, San Miguel J, Flicek P, Gut I, Melnick A, Mitsiades CS, Licht JD, Campo E, Stunnenberg HG, Agirre X, Prosper F, and Martin-Subero JI
- Subjects
- Cell Line, DNA-Binding Proteins metabolism, Epigenesis, Genetic, Humans, NF-kappa B metabolism, Osteogenesis genetics, Receptors, Notch metabolism, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Thioredoxins metabolism, Transcription Factors metabolism, Tumor Suppressor Protein p53 metabolism, Up-Regulation, Chromatin metabolism, Gene Expression Regulation, Neoplastic, Multiple Myeloma genetics, Plasma Cells metabolism
- Abstract
Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin ( TXN ), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype., (© 2020 Ordoñez et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2020
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48. Correction: Ordoñez, et al.; DNA Methylation of Enhancer Elements in Myeloid Neoplasms: Think Outside the Promoters? Cancers 2019, 11, 1424.
- Author
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Ordoñez R, Martínez-Calle N, Agirre X, and Prosper F
- Abstract
The authors would like to make a correction to their published paper [...]., Competing Interests: The authors declare no conflict of interest.
- Published
- 2020
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49. The hydroxymethylome of multiple myeloma identifies FAM72D as a 1q21 marker linked to proliferation.
- Author
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Chatonnet F, Pignarre A, Sérandour AA, Caron G, Avner S, Robert N, Kassambara A, Laurent A, Bizot M, Agirre X, Prosper F, Martin-Subero JI, Moreaux J, Fest T, and Salbert G
- Subjects
- Cell Proliferation genetics, DNA Methylation, Epigenesis, Genetic, Epigenomics, Humans, Multiple Myeloma genetics, Proteins genetics
- Abstract
Cell identity relies on the cross-talk between genetics and epigenetics and their impact on gene expression. Oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) is the first step of an active DNA demethylation process occurring mainly at enhancers and gene bodies and, as such, participates in processes governing cell identity in normal and pathological conditions. Although genetic alterations are well documented in multiple myeloma (MM), epigenetic alterations associated with this disease have not yet been thoroughly analyzed. To gain insight into the biology of MM, genome-wide 5hmC profiles were obtained and showed that regions enriched in this modified base overlap with MM enhancers and super enhancers and are close to highly expressed genes. Through the definition of a MM-specific 5hmC signature, we identified FAM72D as a poor prognostic gene located on 1q21, a region amplified in high risk myeloma. We further uncovered that FAM72D functions as part of the FOXM1 transcription factor network controlling cell proliferation and survival and we evidenced an increased sensitivity of cells expressing high levels of FOXM1 and FAM72 to epigenetic drugs targeting histone deacetylases and DNA methyltransferases., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
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50. Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination.
- Author
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Garcés JJ, Simicek M, Vicari M, Brozova L, Burgos L, Bezdekova R, Alignani D, Calasanz MJ, Growkova K, Goicoechea I, Agirre X, Pour L, Prosper F, Rios R, Martinez-Lopez J, Millacoy P, Palomera L, Del Orbe R, Perez-Montaña A, Garate S, Blanco L, Lasa M, Maiso P, Flores-Montero J, Sanoja-Flores L, Chyra Z, Vdovin A, Sevcikova T, Jelinek T, Botta C, El Omri H, Keats J, Orfao A, Hajek R, San-Miguel JF, and Paiva B
- Subjects
- Bone Marrow pathology, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation genetics, Epithelial-Mesenchymal Transition genetics, Gene Expression genetics, Humans, Hypoxia genetics, Hypoxia pathology, Inflammation genetics, Inflammation pathology, Neoplastic Stem Cells pathology, Prognosis, Tumor Microenvironment genetics, Multiple Myeloma genetics, Multiple Myeloma pathology, Neoplastic Cells, Circulating pathology, Transcription, Genetic genetics
- Abstract
The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r ≥ 0.94, P = 10
-16 ), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial-mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs. The cancer stem cell marker CD44 was overexpressed in CTCs, and its knockdown significantly reduced migration of MM cells towards SDF1-α and their adhesion to fibronectin. Approximately half (29/55) of genes differentially expressed in CTCs were prognostic in patients with newly-diagnosed myeloma (n = 553; CoMMpass). In a multivariate analysis including the R-ISS, overexpression of CENPF and LGALS1 was significantly associated with inferior survival. Altogether, these results help understanding the presence of CTCs in PB and suggest that hypoxic BM niches together with a pro-inflammatory microenvironment induce an arrest in proliferation, forcing tumor cells to circulate in PB and seek other BM niches to continue growing.- Published
- 2020
- Full Text
- View/download PDF
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