Research publications

Found 1518 publicacions matching the indicated search criteria.
Christian Koelsche, Daniel Schrimpf, Damian Stichel, Martin Sill, Felix Sahm, David E. Reuss, Mirjam Blattner, Barbara Worst, Christoph E. Heilig, Katja Beck, Peter Horak, Simon Kreutzfeldt, Elke Paff, Sebastian Stark, Pascal Johann, Florian Selt, Jonas Ecker, Dominik Sturm, Kristian W. Pajtler, Annekathrin Reinhardt, Annika K. Wefers, Philipp Sievers, Azadeh Ebrahimi, Abigail Suwala, Francisco Fernández-Klett, Belén Casalini, Andrey Korshunov, Volker Hovestadt, Felix K. F. Kommoss, Mark Kriegsmann, Matthias Schick, Melanie Bewerunge-Hudler, Till Milde, Olaf Witt, Andreas E. Kulozik, Marcel Kool, Laura Romero-Pérez, Thomas G. P. Grünewald, Thomas Kirchner, Wolfgang Wick, Michael Platten, Andreas Unterberg, Matthias Uhl, Amir Abdollahi, Jürgen Debus, Burkhard Lehner, Christian Thomas, Martin Hasselblatt, Werner Paulus, Christian Hartmann, Ori Staszewski, Marco Prinz, Jürgen Hench, Stephan Frank, Yvonne M. H. Versleijen-Jonkers, Marije E. Weidema, Thomas Mentzel, Klaus Griewank, Enrique de Álava, Juan Díaz Martín, Miguel A. Idoate Gastearena, Kenneth Tou-En Chang, Sharon Yin Yee Low, Adrian Cuevas-Bourdier, Michel Mittelbronn, Martin Mynarek, Stefan Rutkowski, Ulrich Schüller, Viktor F. Mautner, Jens Schittenhelm, Jonathan Serrano, Matija Snuderl, Reinhard Büttner, Thomas Klingebiel, Rolf Buslei, Manfred Gessler, Pieter Wesseling, Winand N. M. Dinjens, Sebastian Brandner, Zane Jaunmuktane, Iben Lyskjær, Peter Schirmacher, Albrecht Stenzinger, Benedikt Brors, Hanno Glimm, Christoph Heining, Oscar M. Tirado, Miguel Sáinz-Jaspeado, Jaume Mora, Javier Alonso, Xavier Garcia del Muro, Sebastian Moran, Esteller M, Jamal K. Benhamida, Marc Ladanyi, Eva Wardelmann, Cristina Antonescu, Adrienne Flanagan, Uta Dirksen, Peter Hohenberger, Daniel Baumhoer, Wolfgang Hartmann, Christian Vokuhl, Uta Flucke, Iver Petersen, Gunhild Mechtersheimer, David Capper, David T. W. Jones, Stefan Fröhling, Stefan M. Pfister & Andreas

Sarcoma classification by DNA methylation profiling

Nature Communications volume 12, Article number: 498 (2021) 21 Jan 2021, .
Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
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Antonio Garcia-Gomez, Tianlu Li, Carlos de la Calle-Fabregat, Javier Rodríguez-Ubreva, Laura Ciudad, Francesc Català-Moll, Gerard Godoy-Tena, Montserrat Martín-Sánchez, Laura San-Segundo, Sandra Muntión, Xabier Morales, Carlos Ortiz-de-Solórzano, Julen Oyarzabal, Edurne San José-Enériz, Manel Esteller, Xabier Agirre, Felipe Prosper, Mercedes Garayoa, Esteban Ballestar

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

Nat Commun 12, 421 (2021) 18 Jan 2021, .
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.
M Cabezón, R Malinverni, B Xicoy, S Marcé, J Bargay, A Garrido, M Tormo, L Arenillas, R Coll, J Borras, M Hoyos, D Valcárcel, L Escoda, F Vall-Llovera, A Garcia, L L Font, E Rámila, M J Jiménez, M Buschbeck, L Zamora, CETLAM group

Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival

2021 Jan 14;13(1):9 14 Jan 2021, .
Background: Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. Results: Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. Conclusions: Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.
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Pamela Acha, Montserrat Hoyos, Marta Pratcorona, Francisco Fuster-Tormo, Laura Palomo, Esther Ortega, Lurdes Zamora, Susana Vives, Isabel Granada, Julia Montoro, Antoni Garcia, Montserrat Arnan, Marta Cervera, Marta Canet, David Gallardo, Leonor Arenillas, Jordi Esteve, Joan Baragay, Olga Salamero, Cristina Motlló, Xavier Ortín, Jordi Sierra, Francesc Solé

Genetic characterization of acute myeloid leukemia patients with mutations in IDH1/2 genes

Leuk Res . 2021 Jan 11;101:106492. 11 Jan 2021, .
Highlights • IDH1/2 cases account for 23% of the studied cohort. • Mutual exclusivity was confirmed for IDH1 and IDH2 mutations. • IDH1 (86%) and IDH2 (89%) mutations frequently constitute an ancestral event.
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Celia González-Gil, Jordi Ribera, Josep Maria Ribera, Eulàlia Genescà

The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia

Genes 2021, 12, 79. 9 Jan 2021, .
Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives initiation, clonal expansion and metastasis. In this process, alterations in genes encoding proteins that govern processes such as cell proliferation, differentiation, and growth provide us with some of the clearest mechanistic insights into how and why cancer arises. In such a scenario, deletions in the 9p21.3 cluster involving CDKN2A/ARF/CDKN2B genes arise as one of the oncogenic hallmarks of ALL. Deletions in this region are the most frequent structural alteration in T-cell acute lymphoblastic leukemia (T-ALL) and account for roughly 30% of copy number alterations found in B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). Here, we review the literature concerning the involvement of the CDKN2A/B genes as a prognosis marker of good or bad response in the two ALL subtypes (BCP-ALL and T-ALL). We compare frequencies observed in studies performed on several ALL cohorts (adult and child), which mainly consider genetic data produced by genomic techniques. We also summarize what we have learned from mouse models designed to evaluate the functional involvement of the gene cluster in ALL development and in relapse/resistance to treatment. Finally, we examine the range of possibilities for targeting the abnormal function of the protein-coding genes of this cluster and their potential to act as anti-leukemic agents in patients.
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Marc Armengol, Juliana Carvalho Santos, Miranda Fernández-Serrano, Núria Profitós-Pelejà, Marcelo Lima Ribeiro, Gaël Roué

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

Cancers 2021, 13(2), 214 8 Jan 2021, .
For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because, in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and build a projection of how the field may evolve in the near future. In particular, we will analyse the current strategies being evaluated both preclinically and clinically, with the aim of fostering the use of immune-checkpoint inhibitors in lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.
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Voltà-Durán E, Serna N, Sánchez-García L, Aviñó A, Sánchez JM, López-Laguna H, Cano-Garrido O, Casanova I, Mangues R, Eritja R, Vázquez E, Villaverde A, Unzueta U.

Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles

Acta Biomater. 2021 Jan 1;119:312-322. 1 Jan 2021, .
The possibility to conjugate tumor-targeted cytotoxic nanoparticles and conventional antitumoral drugs in single pharmacological entities would open a wide spectrum of opportunities in nanomedical oncology. This principle has been explored here by using CXCR4-targeted self-assembling protein nanoparticles based on two potent microbial toxins, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheriae, to which oligo-floxuridine and monomethyl auristatin E respectively have been chemically coupled. The resulting multifunctional hybrid nanoconjugates, with a hydrodynamic size of around 50 nm, are stable and internalize target cells with a biological impact. Although the chemical conjugation minimizes the cytotoxic activity of the protein partner in the complexes, the concept of drug combination proposed here is fully feasible and highly promising when considering multiple drug treatments aimed to higher effectiveness or when facing the therapy of cancers with acquired resistance to classical drugs.
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Carrato C, Alameda F, Esteve-Codina A, Pineda E, Arpí O, Martinez-García M, Mallo M, Gut M, Lopez-Martos R, Barco SD, Ribalta T, Capellades J, Puig J, Gallego O, Mesia C, Muñoz-Marmol AM, Archilla I, Arumí M, Blanc JM, Bellosillo B, Menendez S, Esteve A, Bagué S, Hernandez A, Craven-Bartle J, Fuentes R, Vidal N, Aldecoa I, Iglesia N, Balana C.

Glioblastoma TCGA Mesenchymal and IGS 23 Tumors are Identifiable by IHC and have an Immune-phenotype Indicating a Potential Benefit from Immunotherapy

Clin Cancer Res. 2020 Dec 15;26(24):6600-6609. 15 Dec 2020, .
PURPOSE: Molecular subtype classifications in glioblastoma may detect therapy sensitivities. IHC would potentially allow the identification of molecular subtypes in routine clinical practice.EXPERIMENTAL DESIGN: Formalin-fixed, paraffin-embedded tumor samples of 124 uniformly treated, newly diagnosed patients with glioblastoma were submitted to RNA sequencing, IHC, and immune-phenotyping to identify differences in molecular subtypes associated with treatment sensitivities.RESULTS: We detected high molecular and IHC overlapping of the The Cancer Genome Atlas (TCGA) mesenchymal subtype with instrinsic glioma subtypes (IGS) cluster 23 and of the TCGA classical subtype with IGS cluster 18. IHC patterns, gene fusion profiles, and immune-phenotypes varied across subtypes. IHC revealed that the TCGA classical subtype was identified by high expression of EGFR and low expression of PTEN, while the mesenchymal subtype was identified by low expression of SOX2 and high expression of two antibodies, SHC1 and TCIRG1, selected on the basis of RNA differential transcriptomic expression. The proneural subtype was identified by frequent positive IDH1 expression and high Olig2 and Ki67 expression. Immune-phenotyping showed that mesenchymal and IGS 23 tumors exhibited a higher positive effector cell score, a higher negative suppressor cell score, and lower levels of immune checkpoint molecules. The cell-type deconvolution analysis revealed that these tumors are highly enriched in M2 macrophages, resting memory CD4+ T cells, and activated dendritic cells, indicating that they may be ideal candidates for immunotherapy, especially with anti-M2 and/or dendritic cell vaccination.CONCLUSIONS: There is a subset of tumors, frequently classified as mesenchymal or IGS cluster 23, that may be identified with IHC and could well be optimal candidates for immunotherapy.
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de Barrios O, e Barrios O, Galaras A, Trincado JL, Azagra A, Collazo O, Meler A, Agraz-Doblas A, Bueno C, Ballerini P, Cazzaniga G, Stam RW, Varela I, De Lorenzo P, Valsecchi MG, Hatzis P, Menéndez P, Parra M.

HDAC7 is a major contributor in the pathogenesis of infant t(4;11) proB acute lymphoblastic leukemia.

Leukemia, 2020 1 Dec 2020, .
Not abstract available Find out more: https://www.nature.com/articles/s41375-020-01097-x
Sentís I, Gonzalez S, Genescà E, García-Hernández V, Muiños F, Gonzalez C, López-Arribillaga E, Gonzalez J, Fernandez-Ibarrondo L, Mularoni L, Espinosa L, Bellosillo B, Ribera JM, Bigas A, Gonzalez-Perez A, Lopez-Bigas N

The evolution of relapse of adult T cell acute lymphoblastic leukemia.

Genome Biol. 2020 Nov 23;21(1):284 20 Nov 2020, .
Background: Adult T cell acute lymphoblastic leukemia (T-ALL) is a rare disease that affects less than 10 individuals in one million. It has been less studied than its cognate pediatric malignancy, which is more prevalent. A higher percentage of the adult patients relapse, compared to children. It is thus essential to study the mechanisms of relapse of adult T-ALL cases. Results: We profile whole-genome somatic mutations of 19 primary T-ALLs from adult patients and the corresponding relapse malignancies and analyze their evolution upon treatment in comparison with 238 pediatric and young adult ALL cases. We compare the mutational processes and driver mutations active in primary and relapse adult T-ALLs with those of pediatric patients. A precise estimation of clock-like mutations in leukemic cells shows that the emergence of the relapse clone occurs several months before the diagnosis of the primary T-ALL. Specifically, through the doubling time of the leukemic population, we find that in at least 14 out of the 19 patients, the population of relapse leukemia present at the moment of diagnosis comprises more than one but fewer than 108 blasts. Using simulations, we show that in all patients the relapse appears to be driven by genetic mutations. Conclusions: The early appearance of a population of leukemic cells with genetic mechanisms of resistance across adult T-ALL cases constitutes a challenge for treatment. Improving early detection of the malignancy is thus key to prevent its relapse. Keywords: T-ALL, Adult acute lymphoblastic leukemia, T-ALL evolution under therapy, Evolution of leukemia relapse, ALL relapse