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1. IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia

Author

Fundación la Caixa, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Generalitat de Catalunya, National Institutes of Health (US), National Cancer Institute (US), Centro de Investigación Biomédica en Red Cáncer (España), Ministerio de Universidades (España), Fundación Científica Asociación Española Contra el Cáncer, National Heart, Lung, and Blood Institute (US), American Association for Cancer Research, Lady Tata Memorial Trust, Institución Catalana de Investigación y Estudios Avanzados, Centro Esther Koplowitz, Syrykh, Charlotte, Pons-Brun, Berta, Russiñol, Núria, Playa-Albinyana, Heribert, Baumann, Tycho, Duran-Ferrer, Martí, Kulis, Marta, Carbó-Meix, Anna, Mozas, Pablo, Alcoceba, Miguel, González, Marcos, Navarro-Bailón, Almudena, Colado, Enrique, Payer, Ángel R., Aymerich, Marta, Terol, María J., Lu, Junyan, Knisbacher, Binyamin A., Hahn, Cynthia K., Ruiz-Gaspà, Sílvia, Enjuanes, Anna, Wu, Catherine J., Getz, Gad, Zenz, Thorsten, López-Guillermo, Armando, Martín-Subero, José I., Colomer, Dolors, Delgado, Julio, Campo, Elías, Nadeu, Ferran, Fundación la Caixa, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Generalitat de Catalunya, National Institutes of Health (US), National Cancer Institute (US), Centro de Investigación Biomédica en Red Cáncer (España), Ministerio de Universidades (España), Fundación Científica Asociación Española Contra el Cáncer, National Heart, Lung, and Blood Institute (US), American Association for Cancer Research, Lady Tata Memorial Trust, Institución Catalana de Investigación y Estudios Avanzados, Centro Esther Koplowitz, Syrykh, Charlotte, Pons-Brun, Berta, Russiñol, Núria, Playa-Albinyana, Heribert, Baumann, Tycho, Duran-Ferrer, Martí, Kulis, Marta, Carbó-Meix, Anna, Mozas, Pablo, Alcoceba, Miguel, González, Marcos, Navarro-Bailón, Almudena, Colado, Enrique, Payer, Ángel R., Aymerich, Marta, Terol, María J., Lu, Junyan, Knisbacher, Binyamin A., Hahn, Cynthia K., Ruiz-Gaspà, Sílvia, Enjuanes, Anna, Wu, Catherine J., Getz, Gad, Zenz, Thorsten, López-Guillermo, Armando, Martín-Subero, José I., Colomer, Dolors, Delgado, Julio, Campo, Elías, and Nadeu, Ferran

Abstract

Chronic lymphocytic leukemia (CLL) has high biological and clinical heterogeneity.1,2 A few prognostic factors are used in clinical practice, including immunoglobulin heavy-chain variable (IGHV) gene somatic hypermutation (SHM) status, chromosome aberrations, and gene mutations, which remain insufficient for personalized patient management.3,4 Recent studies have shown that expression of the immunoglobulin lambda light chain IGLV3-21 gene carrying an SHM-derived G>C mutation changing the glycine at position 110 to an arginine (IGLV3-21R110) defines a subset of CLL with an intermediate epigenetic profile and an aggressive clinical course.5,6 When occurring on the IGLV3-21∗01 or ∗04 alleles, the R110 mutation allows homotypic B-cell receptor (BCR) interactions, triggering cell-autonomous BCR signaling5,7 and/or facilitating T-cell–independent engagement with superantigen.8 IGLV3-21R110 has been detected in up to 6.5% of patients with CLL at diagnosis and in up to 25% of patients enrolled in clinical trials.5,6,9 We6 and others5 have shown that all CLL cases belonging to aggressive stereotyped subset #2 carried the IGLV3-21R110. Nonetheless, approximately half of IGLV3-21R110 CLL are not classified as stereotyped subset #2 but seem to have a similar clinical outcome,5,6 suggesting that the conventional stereotyped subset #2 classification might not completely recognize this clinically aggressive subgroup of CLL. In addition, IGLV3-21R110 seems to have a prognostic value independent of the IGHV gene SHM status and methylation–based epigenetic subtypes.5,6 However, further studies in independent cohorts are needed to support its application in clinical practice.1,2,10-12 The aim of this study was to assess the prognostic value of IGLV3-21R110 in large and independent population-based cohorts of patients with CLL.

Published
2023

2. Genomic landscape of follicular lymphoma across a wide spectrum of clinical behaviors

Author

Fundació La Marató de TV3, Fundación Científica Asociación Española Contra el Cáncer, Generalitat de Catalunya, Instituto de Salud Carlos III, European Commission, Centro Esther Koplowitz, Hospital Clínic de Barcelona, Mozas, Pablo, López, Cristina, Grau, Marta, Nadeu, Ferran, Clot, Guillem, Valle, Sara, Kulis, Marta, Navarro, Alba, Ramis-Zaldivar, Joan Enric, González-Farré, Blanca, Rivas-Delgado, Alfredo, Rivero, Andrea, Frigola, Gerard, Balagué, Olga, Giné, Eva, Delgado, Julio, Villamor, Neus, Matutes, Estella, Magnano, Laura, García-Sanz, Ramón, Huet, Sarah, Russell, Robert B., Campo, Elías, López-Guillermo, Armando, Beà, Sílvia, Fundació La Marató de TV3, Fundación Científica Asociación Española Contra el Cáncer, Generalitat de Catalunya, Instituto de Salud Carlos III, European Commission, Centro Esther Koplowitz, Hospital Clínic de Barcelona, Mozas, Pablo, López, Cristina, Grau, Marta, Nadeu, Ferran, Clot, Guillem, Valle, Sara, Kulis, Marta, Navarro, Alba, Ramis-Zaldivar, Joan Enric, González-Farré, Blanca, Rivas-Delgado, Alfredo, Rivero, Andrea, Frigola, Gerard, Balagué, Olga, Giné, Eva, Delgado, Julio, Villamor, Neus, Matutes, Estella, Magnano, Laura, García-Sanz, Ramón, Huet, Sarah, Russell, Robert B., Campo, Elías, López-Guillermo, Armando, and Beà, Sílvia

Abstract

While some follicular lymphoma (FL) patients do not require treatment or experience prolonged responses, others relapse early, and little is known about genetic alterations specific to patients with a particular clinical behavior. We selected 56 grade 1–3A FL patients according to their need of treatment or timing of relapse: never treated (n = 7), non-relapsed (19), late relapse (14), early relapse or POD24 (11), and primary refractory (5). We analyzed 56 diagnostic and 12 paired relapse lymphoid tissue biopsies and performed copy number alteration (CNA) analysis and next generation sequencing (NGS). We identified six focal driver losses (1p36.32, 6p21.32, 6q14.1, 6q23.3, 9p21.3, 10q23.33) and 1p36.33 copy-neutral loss of heterozygosity (CN-LOH). By integrating CNA and NGS results, the most frequently altered genes/regions were KMT2D (79%), CREBBP (67%), TNFRSF14 (46%) and BCL2 (40%). Although we found that mutations in PIM1, FOXO1 and TMEM30A were associated with an adverse clinical behavior, definitive conclusions cannot be drawn, due to the small sample size. We identified common precursor cells harboring early oncogenic alterations of the KMT2D, CREBBP, TNFRSF14 and EP300 genes and 16p13.3-p13.2 CN-LOH. Finally, we established the functional consequences of mutations by means of protein modeling (CD79B, PLCG2, PIM1, MCL1 and IRF8). These data expand the knowledge on the genomics behind the heterogeneous FL population and, upon replication in larger cohorts, could contribute to risk stratification and the development of targeted therapies.

Published
2023

3. IGLV3-21$^{R110}$ mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia

Author

Nadeu, Ferran; https://orcid.org/0000-0003-2910-9440, Syrykh, Charlotte, Pons-Brun, Berta, Russiñol, Núria, Playa-Albinyana, Heribert; https://orcid.org/0000-0002-3447-3848, Baumann, Tycho Stephan, Duran-Ferrer, Martí; https://orcid.org/0000-0003-1666-5819, Kulis, Marta; https://orcid.org/0000-0001-8104-9620, Carbó-Meix, Anna, Mozas, Pablo; https://orcid.org/0000-0001-9528-4971, Alcoceba, Miguel, González, Marcos; https://orcid.org/0000-0001-6637-1072, Navarro-Bailón, Almudena; https://orcid.org/0000-0002-7972-5666, Colado, Enrique, Payer, Ángel, Aymerich, Marta, Terol, María José, Lu, Junyan; https://orcid.org/0000-0002-9211-0746, Knisbacher, Binyamin Asher; https://orcid.org/0000-0002-4962-9956, Hahn, Cynthia K; https://orcid.org/0000-0001-8284-7261, Ruiz-Gaspà, Sílvia, Enjuanes, Anna, Wu, Catherine J; https://orcid.org/0000-0002-3348-5054, Getz, Gad, Zenz, Thorsten; https://orcid.org/0000-0001-7890-9845, López-Guillermo, Armando, Martin-Subero, Jose I; https://orcid.org/0000-0001-8809-5195, Colomer, Dolors, Delgado, Julio; https://orcid.org/0000-0002-5157-4376, Campo, Elías; https://orcid.org/0000-0001-9850-9793, Nadeu, Ferran; https://orcid.org/0000-0003-2910-9440, Syrykh, Charlotte, Pons-Brun, Berta, Russiñol, Núria, Playa-Albinyana, Heribert; https://orcid.org/0000-0002-3447-3848, Baumann, Tycho Stephan, Duran-Ferrer, Martí; https://orcid.org/0000-0003-1666-5819, Kulis, Marta; https://orcid.org/0000-0001-8104-9620, Carbó-Meix, Anna, Mozas, Pablo; https://orcid.org/0000-0001-9528-4971, Alcoceba, Miguel, González, Marcos; https://orcid.org/0000-0001-6637-1072, Navarro-Bailón, Almudena; https://orcid.org/0000-0002-7972-5666, Colado, Enrique, Payer, Ángel, Aymerich, Marta, Terol, María José, Lu, Junyan; https://orcid.org/0000-0002-9211-0746, Knisbacher, Binyamin Asher; https://orcid.org/0000-0002-4962-9956, Hahn, Cynthia K; https://orcid.org/0000-0001-8284-7261, Ruiz-Gaspà, Sílvia, Enjuanes, Anna, Wu, Catherine J; https://orcid.org/0000-0002-3348-5054, Getz, Gad, Zenz, Thorsten; https://orcid.org/0000-0001-7890-9845, López-Guillermo, Armando, Martin-Subero, Jose I; https://orcid.org/0000-0001-8809-5195, Colomer, Dolors, Delgado, Julio; https://orcid.org/0000-0002-5157-4376, and Campo, Elías; https://orcid.org/0000-0001-9850-9793

Published
2023

4. Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue

Author

Gonzalez-Franquesa, Alba, Gama-Perez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernandez-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miro-Blanch, Joan, Oemer, Gregor, Duran, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castano, Carlos, Novials, Anna, Gomis, Ramon, Monsalve, Maria, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernandez-Veledo, Sonia, Antonio Enriquez, Jose, Carracedo, Angel, Carlos Perales, Jose, Nogueiras, Ruben, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Oscar, Sales-Pardo, Marta, Guimera, Roger, Blueher, Matthias, Ignacio Martin-Subero, Jose, Garcia-Roves, Pablo M., Gonzalez-Franquesa, Alba, Gama-Perez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernandez-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miro-Blanch, Joan, Oemer, Gregor, Duran, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castano, Carlos, Novials, Anna, Gomis, Ramon, Monsalve, Maria, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernandez-Veledo, Sonia, Antonio Enriquez, Jose, Carracedo, Angel, Carlos Perales, Jose, Nogueiras, Ruben, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Oscar, Sales-Pardo, Marta, Guimera, Roger, Blueher, Matthias, Ignacio Martin-Subero, Jose, and Garcia-Roves, Pablo M.

Abstract

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Published
2022

5. Supplementary files of the article 'Detection of early seeding of Richter transformation in chronic lymphocytic leukemia' [Dataset]

Author

Nadeu, Ferran, Royo, Romina, Massoni-Badosa, Ramon, Playa-Albinyana, Heribert, Garcia-Torre, Beatriz, Duran-Ferrer, Martí, Dawson, Kevin J., Kulis, Marta, Diaz-Navarro, Ander, Villamor, Neus, Melero, Juan L., Chapaprieta, Vicente, Dueso-Barroso, Ana, Delgado, Julio, Moia, Riccardo, Ruiz-Gil, Sara, Marchese, Domenica, Giró, Ariadna, Verdaguer-Dot, Núria, Romo, Mónica, Clot, Guillem, Rozman, María, Frigola, Gerard, Rivas-Delgado, Alfredo, Baumann, Tycho, Alcoceba, Miguel, González, Marcos, Climent, Fina, Abrisqueta, Pau, Castellví, Josep, Bosch, Francesc, Aymerich, Marta, Enjuanes, Anna, Ruiz-Gaspà, Sílvia, López-Guillermo, Armando, Jares, Pedro, Beà, Silvia, Capella-Gutiérrez, Salvador, Gelpí, Josep Lluis, López-Bigas, Nuria, Torrents, David, Campbell, Peter J., Gut, Ivo, Rossi, Davide, Gaidano, Gianluca, Puente, Xose S., García-Roves, Pablo M., Colomer, Dolors, Heyn, Holger, Maura, Francesco, Martín-Subero, José Ignacio, Campo, Elías, Nadeu, Ferran, Royo, Romina, Massoni-Badosa, Ramon, Playa-Albinyana, Heribert, Garcia-Torre, Beatriz, Duran-Ferrer, Martí, Dawson, Kevin J., Kulis, Marta, Diaz-Navarro, Ander, Villamor, Neus, Melero, Juan L., Chapaprieta, Vicente, Dueso-Barroso, Ana, Delgado, Julio, Moia, Riccardo, Ruiz-Gil, Sara, Marchese, Domenica, Giró, Ariadna, Verdaguer-Dot, Núria, Romo, Mónica, Clot, Guillem, Rozman, María, Frigola, Gerard, Rivas-Delgado, Alfredo, Baumann, Tycho, Alcoceba, Miguel, González, Marcos, Climent, Fina, Abrisqueta, Pau, Castellví, Josep, Bosch, Francesc, Aymerich, Marta, Enjuanes, Anna, Ruiz-Gaspà, Sílvia, López-Guillermo, Armando, Jares, Pedro, Beà, Silvia, Capella-Gutiérrez, Salvador, Gelpí, Josep Lluis, López-Bigas, Nuria, Torrents, David, Campbell, Peter J., Gut, Ivo, Rossi, Davide, Gaidano, Gianluca, Puente, Xose S., García-Roves, Pablo M., Colomer, Dolors, Heyn, Holger, Maura, Francesco, Martín-Subero, José Ignacio, and Campo, Elías

Published
2022

6. Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Generalitat de Catalunya, Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, European Foundation for the Study of Diabetes, Novo Nordisk Foundation, European Commission, Centro Esther Koplowitz, González-Franquesa, Alba, Gama-Pérez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernández-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miró-Blanch, Joan, Oemer, Gregor, Durán, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castaño, Carlos, Novials, Anna, Gomis, Ramón, Monsalve, María, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernández-Veledo, Sonia, Enríquez, José Antonio, Perales, José Carlos, Nogueiras, Rubén, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Óscar, Sales-Pardo, Marta, Guimerà, Roger, Blüher, Matthias, Martín-Subero, José Ignacio, Garcia-Roves, Pablo M., Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Generalitat de Catalunya, Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, European Foundation for the Study of Diabetes, Novo Nordisk Foundation, European Commission, Centro Esther Koplowitz, González-Franquesa, Alba, Gama-Pérez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernández-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miró-Blanch, Joan, Oemer, Gregor, Durán, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castaño, Carlos, Novials, Anna, Gomis, Ramón, Monsalve, María, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernández-Veledo, Sonia, Enríquez, José Antonio, Perales, José Carlos, Nogueiras, Rubén, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Óscar, Sales-Pardo, Marta, Guimerà, Roger, Blüher, Matthias, Martín-Subero, José Ignacio, and Garcia-Roves, Pablo M.

Abstract

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Published
2022

7. Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

Author

Fundación la Caixa, European Research Council, European Commission, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), American Association for Cancer Research, European Hematology Association, Lady Tata Memorial Trust, Generalitat de Catalunya, Asociación Española Contra el Cáncer, Fundació La Marató de TV3, Centro de Investigación Biomédica en Red Cáncer (España), Fundación Científica Asociación Española Contra el Cáncer, Associazione Italiana per la Ricerca sul Cancro, Eusko Jaurlaritza, Nadeu, Ferran, Royo, Romina, Massoni-Badosa, Ramon, Playa-Albinyana, Heribert, Garcia-Torre, Beatriz, Duran-Ferrer, Martí, Dawson, Kevin J., Kulis, Marta, Diaz-Navarro, Ander, Villamor, Neus, Melero, Juan L., Chapaprieta, Vicente, Dueso-Barroso, Ana, Delgado, Julio, Moia, Riccardo, Ruiz-Gil, Sara, Marchese, Domenica, Giró, Ariadna, Verdaguer-Dot, Núria, Romo, Mónica, Clot, Guillem, Rozman, María, Frigola, Gerard, Rivas-Delgado, Alfredo, Baumann, Tycho, Alcoceba, Miguel, González, Marcos, Climent, Fina, Abrisqueta, Pau, Castellví, Josep, Bosch, Francesc, Aymerich, Marta, Enjuanes, Anna, Ruiz-Gaspà, Sílvia, López-Guillermo, Armando, Jares, Pedro, Beà, Silvia, Capella-Gutiérrez, Salvador, Gelpí, Josep Lluis, López-Bigas, Nuria, Torrents, David, Campbell, Peter J., Gut, Ivo, Rossi, Davide, Gaidano, Gianluca, Puente, Xose S., García-Roves, Pablo M., Colomer, Dolors, Heyn, Holger, Maura, Francesco, Martín-Subero, José Ignacio, Campo, Elías, Fundación la Caixa, European Research Council, European Commission, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), American Association for Cancer Research, European Hematology Association, Lady Tata Memorial Trust, Generalitat de Catalunya, Asociación Española Contra el Cáncer, Fundació La Marató de TV3, Centro de Investigación Biomédica en Red Cáncer (España), Fundación Científica Asociación Española Contra el Cáncer, Associazione Italiana per la Ricerca sul Cancro, Eusko Jaurlaritza, Nadeu, Ferran, Royo, Romina, Massoni-Badosa, Ramon, Playa-Albinyana, Heribert, Garcia-Torre, Beatriz, Duran-Ferrer, Martí, Dawson, Kevin J., Kulis, Marta, Diaz-Navarro, Ander, Villamor, Neus, Melero, Juan L., Chapaprieta, Vicente, Dueso-Barroso, Ana, Delgado, Julio, Moia, Riccardo, Ruiz-Gil, Sara, Marchese, Domenica, Giró, Ariadna, Verdaguer-Dot, Núria, Romo, Mónica, Clot, Guillem, Rozman, María, Frigola, Gerard, Rivas-Delgado, Alfredo, Baumann, Tycho, Alcoceba, Miguel, González, Marcos, Climent, Fina, Abrisqueta, Pau, Castellví, Josep, Bosch, Francesc, Aymerich, Marta, Enjuanes, Anna, Ruiz-Gaspà, Sílvia, López-Guillermo, Armando, Jares, Pedro, Beà, Silvia, Capella-Gutiérrez, Salvador, Gelpí, Josep Lluis, López-Bigas, Nuria, Torrents, David, Campbell, Peter J., Gut, Ivo, Rossi, Davide, Gaidano, Gianluca, Puente, Xose S., García-Roves, Pablo M., Colomer, Dolors, Heyn, Holger, Maura, Francesco, Martín-Subero, José Ignacio, and Campo, Elías

Abstract

Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high–B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.

Published
2022

8. Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue

Author

Gonzalez-Franquesa, Alba, Gama-Perez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernández-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miró-Blanch, Joan, Oemer, Gregor, Duran, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castaño, Carlos, Novials, Anna, Gomis, Ramon, Monsalve, Maria, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernández-Veledo, Sonia, Enríquez, Jose Antonio, Carracedo, Angel, Perales, José Carlos, Nogueiras, Rubén, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Oscar, Sales-Pardo, Marta, Guimerà, Roger, Blüher, Matthias, Martín-Subero, José Ignacio, Garcia-Roves, Pablo M., Gonzalez-Franquesa, Alba, Gama-Perez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernández-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miró-Blanch, Joan, Oemer, Gregor, Duran, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castaño, Carlos, Novials, Anna, Gomis, Ramon, Monsalve, Maria, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernández-Veledo, Sonia, Enríquez, Jose Antonio, Carracedo, Angel, Perales, José Carlos, Nogueiras, Rubén, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Oscar, Sales-Pardo, Marta, Guimerà, Roger, Blüher, Matthias, Martín-Subero, José Ignacio, and Garcia-Roves, Pablo M.

Abstract

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Published
2022

9. Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue

Author

Gonzalez-Franquesa, Alba, Gama-Perez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernández-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miró-Blanch, Joan, Oemer, Gregor, Duran, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castaño, Carlos, Novials, Anna, Gomis, Ramon, Monsalve, Maria, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernández-Veledo, Sonia, Enríquez, Jose Antonio, Carracedo, Angel, Perales, José Carlos, Nogueiras, Rubén, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Oscar, Sales-Pardo, Marta, Guimerà, Roger, Blüher, Matthias, Martín-Subero, José Ignacio, Garcia-Roves, Pablo M., Gonzalez-Franquesa, Alba, Gama-Perez, Pau, Kulis, Marta, Szczepanowska, Karolina, Dahdah, Norma, Moreno-Gomez, Sonia, Latorre-Pellicer, Ana, Fernández-Ruiz, Rebeca, Aguilar-Mogas, Antoni, Hoffman, Anne, Monelli, Erika, Samino, Sara, Miró-Blanch, Joan, Oemer, Gregor, Duran, Xavier, Sanchez-Rebordelo, Estrella, Schneeberger, Marc, Obach, Merce, Montane, Joel, Castellano, Giancarlo, Chapaprieta, Vicente, Sun, Wenfei, Navarro, Lourdes, Prieto, Ignacio, Castaño, Carlos, Novials, Anna, Gomis, Ramon, Monsalve, Maria, Claret, Marc, Graupera, Mariona, Soria, Guadalupe, Wolfrum, Christian, Vendrell, Joan, Fernández-Veledo, Sonia, Enríquez, Jose Antonio, Carracedo, Angel, Perales, José Carlos, Nogueiras, Rubén, Herrero, Laura, Trifunovic, Aleksandra, Keller, Markus A., Yanes, Oscar, Sales-Pardo, Marta, Guimerà, Roger, Blüher, Matthias, Martín-Subero, José Ignacio, and Garcia-Roves, Pablo M.

Abstract

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Published
2022

10. The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome

Author

Duran-Ferrer, Marti, Clot, Guillem, Nadeu, Ferran, Beekman, Renee, Baumann, Tycho, Nordlund, Jessica, Marincevic-Zuniga, Yanara, Lönnerholm, Gudmar, Rivas-Delgado, Alfredo, Martin, Silvia, Ordonez, Raquel, Castellano, Giancarlo, Kulis, Marta, Queiros, Ana C., Lee, Seung-Tae, Wiemels, Joseph, Royo, Romina, Puiggros, Montserrat, Lu, Junyan, Gine, Eva, Bea, Silvia, Jares, Pedro, Agirre, Xabier, Prosper, Felipe, Lopez-Otin, Carlos, Puente, Xose S., Oakes, Christopher C., Zenz, Thorsten, Delgado, Julio, Lopez-Guillermo, Armando, Campo, Elias, Ignacio Martin-Subero, Jose, Duran-Ferrer, Marti, Clot, Guillem, Nadeu, Ferran, Beekman, Renee, Baumann, Tycho, Nordlund, Jessica, Marincevic-Zuniga, Yanara, Lönnerholm, Gudmar, Rivas-Delgado, Alfredo, Martin, Silvia, Ordonez, Raquel, Castellano, Giancarlo, Kulis, Marta, Queiros, Ana C., Lee, Seung-Tae, Wiemels, Joseph, Royo, Romina, Puiggros, Montserrat, Lu, Junyan, Gine, Eva, Bea, Silvia, Jares, Pedro, Agirre, Xabier, Prosper, Felipe, Lopez-Otin, Carlos, Puente, Xose S., Oakes, Christopher C., Zenz, Thorsten, Delgado, Julio, Lopez-Guillermo, Armando, Campo, Elias, and Ignacio Martin-Subero, Jose

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 individual-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. 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 differential diagnosis and the prediction of clinical outcome. Martin-Subero and colleagues analyze DNA methylation patterns in B-cell tumors and their normal cells of origin, and develop epiCMIT, a methylation-based mitotic clock with prognostic relevance.

Published
2020
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11. Whole-genome fingerprint of the DNA methylome during human B cell differentiation.

Author

Kulis, Marta, Kulis, Marta, Merkel, Angelika, Heath, Simon, Queirós, Ana C, Schuyler, Ronald P, Castellano, Giancarlo, Beekman, Renée, Raineri, Emanuele, Esteve, Anna, Clot, Guillem, Verdaguer-Dot, Néria, Duran-Ferrer, Martí, Russiñol, Nuria, Vilarrasa-Blasi, Roser, Ecker, Simone, Pancaldi, Vera, Rico, Daniel, Agueda, Lidia, Blanc, Julie, Richardson, David, Clarke, Laura, Datta, Avik, Pascual, Marien, Agirre, Xabier, Prosper, Felipe, Alignani, Diego, Paiva, Bruno, Caron, Gersende, Fest, Thierry, Muench, Marcus O, Fomin, Marina E, Lee, Seung-Tae, Wiemels, Joseph L, Valencia, Alfonso, Gut, Marta, Flicek, Paul, Stunnenberg, Hendrik G, Siebert, Reiner, Küppers, Ralf, Gut, Ivo G, Campo, Elías, Martín-Subero, José I, Kulis, Marta, Kulis, Marta, Merkel, Angelika, Heath, Simon, Queirós, Ana C, Schuyler, Ronald P, Castellano, Giancarlo, Beekman, Renée, Raineri, Emanuele, Esteve, Anna, Clot, Guillem, Verdaguer-Dot, Néria, Duran-Ferrer, Martí, Russiñol, Nuria, Vilarrasa-Blasi, Roser, Ecker, Simone, Pancaldi, Vera, Rico, Daniel, Agueda, Lidia, Blanc, Julie, Richardson, David, Clarke, Laura, Datta, Avik, Pascual, Marien, Agirre, Xabier, Prosper, Felipe, Alignani, Diego, Paiva, Bruno, Caron, Gersende, Fest, Thierry, Muench, Marcus O, Fomin, Marina E, Lee, Seung-Tae, Wiemels, Joseph L, Valencia, Alfonso, Gut, Marta, Flicek, Paul, Stunnenberg, Hendrik G, Siebert, Reiner, Küppers, Ralf, Gut, Ivo G, Campo, Elías, and Martín-Subero, José I

Abstract

We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.

Published
2015

12. Quantitative comparison of DNA methylation assays for biomarker development and clinical applications

Author

Biotechnology and Biological Sciences Research Council (UK), Federal Ministry of Education and Research (Germany), National Institute of Mental Health (US), European Commission, Deutsches Krebsforschungszentrum, Bock, Christoph, Halbritter, Florian, Carmona, Francisco J., Tierling, Sascha, Datlinger, Paul, Assenov, Yassen, Berdasco, María, Bergmann, Anke K., Booher, Keith, Busato, Florence, Campan, Mihaela, Dahl, Christina, Dahmcke, Christina M., Diep, Dinh, Fernández, Agustín F., Gerhauser, Clarissa, Haake, Andrea, Heilmann, Katharina, Holcomb, Thomas, Hussmann, Dianna, Ito, Mitsuteru, Kläver, Ruth, Kreutz, Martin, Kulis, Marta, López, Virginia, Nair, Shalima S., Paul, Dirk S., Plongthongkum, Nongluk, Qu, Wenjia, Queirós, Ana C., Reinicke, Frank, Sauter, Guido, Schlomm, Thorsten, Statham, Aaron, Stirzaker, Clare, Strogantsev, Ruslan, Urdinguio, Rocío G., Walter, Kimberly, Weichenhan, Dieter, Weisenberger, Daniel J., Beck, Stephan, Clark, Susan J., Esteller, Manel, Ferguson-Smith, Anne C., Fraga, Mario F., Guldberg, Per, Lotte Hansen, Lise, Laird, Peter W., Martín, José Ignacio, Nygren, Anders O. H., Peist, Ralf, Plass, Christoph, Shames, David S., Siebert, Reiner, Sun, Xueguang, Tost, Jörg, Walter, Jörn, Zhang, Kun, Biotechnology and Biological Sciences Research Council (UK), Federal Ministry of Education and Research (Germany), National Institute of Mental Health (US), European Commission, Deutsches Krebsforschungszentrum, Bock, Christoph, Halbritter, Florian, Carmona, Francisco J., Tierling, Sascha, Datlinger, Paul, Assenov, Yassen, Berdasco, María, Bergmann, Anke K., Booher, Keith, Busato, Florence, Campan, Mihaela, Dahl, Christina, Dahmcke, Christina M., Diep, Dinh, Fernández, Agustín F., Gerhauser, Clarissa, Haake, Andrea, Heilmann, Katharina, Holcomb, Thomas, Hussmann, Dianna, Ito, Mitsuteru, Kläver, Ruth, Kreutz, Martin, Kulis, Marta, López, Virginia, Nair, Shalima S., Paul, Dirk S., Plongthongkum, Nongluk, Qu, Wenjia, Queirós, Ana C., Reinicke, Frank, Sauter, Guido, Schlomm, Thorsten, Statham, Aaron, Stirzaker, Clare, Strogantsev, Ruslan, Urdinguio, Rocío G., Walter, Kimberly, Weichenhan, Dieter, Weisenberger, Daniel J., Beck, Stephan, Clark, Susan J., Esteller, Manel, Ferguson-Smith, Anne C., Fraga, Mario F., Guldberg, Per, Lotte Hansen, Lise, Laird, Peter W., Martín, José Ignacio, Nygren, Anders O. H., Peist, Ralf, Plass, Christoph, Shames, David S., Siebert, Reiner, Sun, Xueguang, Tost, Jörg, Walter, Jörn, and Zhang, Kun

Abstract

DNA methylation patterns are altered in numerous diseases and often correlate with clinically relevant information such as disease subtypes, prognosis and drug response. With suitable assays and after validation in large cohorts, such associations can be exploited for clinical diagnostics and personalized treatment decisions. Here we describe the results of a community-wide benchmarking study comparing the performance of all widely used methods for DNA methylation analysis that are compatible with routine clinical use. We shipped 32 reference samples to 18 laboratories in seven different countries. Researchers in those laboratories collectively contributed 21 locus-specific assays for an average of 27 predefined genomic regions, as well as six global assays. We evaluated assay sensitivity on low-input samples and assessed the assays' ability to discriminate between cell types. Good agreement was observed across all tested methods, with amplicon bisulfite sequencing and bisulfite pyrosequencing showing the best all-round performance. Our technology comparison can inform the selection, optimization and use of DNA methylation assays in large-scale validation studies, biomarker development and clinical diagnostics.

Published
2016

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