Publicaciones científicas

Se han encontrado 33 publicaciones con los criterios indicados.
Esteller, M, Ferrer, G, Rosselló, M

Epitranscriptomics in Hematopoiesis and Hematologic Malignancies.

Blood Cancer Discovery 22 Jun 2020, .
Since the 1960s, a large number of chemical modifications have been identified in RNA molecules, establishing the RNA epigenetics field named “epitranscriptomics.” These chemical marks participate in several RNA metabolic processes; however, the biological relevance of many of these modifications and the many enzymes involved in their function is not completely understood. Emerging knowledge of the epitranscriptome (pseudouridine, N6-methyladenosine, and A-to-I editing) in hematopoiesis and hematologic malignancies reveals the requirement of these modifications in normal development and their alteration in disorders, leading to the development of new molecules and strategies to target the epitranscriptome as a novel therapeutic approach. RNA modifications are required for the correct development of hematopoietic cells, and their alteration can promote the development of malignancies or the transition from a low-grade to an aggressive disease. While we are expanding our understanding of the epitranscriptome of normal and malignant hematopoiesis, the number of potential new therapeutic interventions is rising.
Blecua P, Martinez-Verbo L, Esteller M

The DNA methylation landscape of hematological malignancies: an update.

Mol Oncol 11 Jun 2020, . Epub 11 Jun 2020
The rapid advances in high-throughput sequencing technologies have made it more evident that epigenetic modifications orchestrate a plethora of complex biological processes. During the last decade, we have gained significant knowledge about a wide range of epigenetic changes that crucially contribute to some of the most aggressive forms of leukemia, lymphoma and myelodysplastic syndromes. DNA methylation is a key epigenetic player in the abnormal initiation, development and progression of these malignancies, often acting in synergy with other epigenetic alterations. It also contributes to the acquisition of drug resistance. In this review, we summarize the role of DNA methylation in hematological malignancies described in the current literature. We discuss in detail the dual role of DNA methylation in normal and aberrant hematopoiesis, as well as the involvement of this type of epigenetic change in other aspects of the disease. Finally, we present a comprehensive overview of the main clinical implications, including a discussion of the therapeutic strategies that regulate or reverse aberrant DNA methylation patterns in hematological malignancies, including their combination with (chemo-) immunotherapy.
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Cossío FP, Esteller M, Berdasco M

Towards a more precise therapy in cancer: Exploring epigenetic complexity.

Curr Opin Chem Biol 29 May 2020, 57 41-49. Epub 29 May 2020
A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. Nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. In this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. Specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. By exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours.
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Joshi R, Castro De Moura M, Piñeyro D, Alvarez-Errico D, Arribas C, Esteller M

The DNA methylation landscape of human cancer organoids available at the American type culture collection.

Epigenetics 12 May 2020, 1-11. Epub 12 May 2020
One caveat in cancer research is the dependence of certain experimental systems that might not really reflect the properties of the primary tumours. The recent irruption of 3D cultured cells termed organoids could render a better representation of the original tumour sample. However, every laboratory has its own protocol and tissue-provider to establish these cancer models, preventing further dissemination and validation of the obtained data. To address this problem, the Human Cancer Models Initiative (HCMI) has selected the American Type Culture Collection (ATCC) to make available organoid models to the scientific community. In this regard, no epigenetic information is available for these samples and, overall, the DNA methylation profiles of human cancer organoids are largely unknown. Herein, we provide the DNA methylation landscape of 25 human cancer organoids available at the ATCC using a microarray that interrogates more than 850,000 CpG sites. We observed that the studied organoids retain the epigenetic setting of their original primary cancer type; that exhibit a DNA methylation landscape characteristic of transformed tissues excluding an overgrowth of normal-matched cells; and that are closer to the DNA methylation profiles of the corresponding primary tumours than to established 2D cell lines. Most importantly, the obtained DNA methylation results are freely available to everyone for further data mining. Thus, our findings support from the epigenetic standpoint that the ATCC human cancer organoids recapitulate many of the features of the disorder in the patient and are excellent tools to be shared among investigators for further tumour biology research.
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Massoni-Badosa R, Iacono G, Moutinho C, Kulis M, Palau N, Marchese D, Rodríguez-Ubreva J, Ballestar E, Rodriguez-Esteban G, Marsal S, Aymerich M, Colomer D, Campo E, Julià A, Martín-Subero JI, Heyn H

Sampling time-dependent artifacts in single-cell genomics studies.

Genome Biol. 11 May 2020, 21 (1) 112. Epub 11 May 2020
Robust protocols and automation now enable large-scale single-cell RNA and ATAC sequencing experiments and their application on biobank and clinical cohorts. However, technical biases introduced during sample acquisition can hinder solid, reproducible results, and a systematic benchmarking is required before entering large-scale data production. Here, we report the existence and extent of gene expression and chromatin accessibility artifacts introduced during sampling and identify experimental and computational solutions for their prevention.
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Gutiérrez-García G, Rovira M, Arab N, Gallego C, Sánchez J, Ángeles Álvarez M, Ayora P, Domenech A, Borràs N, Gerardo Rodríguez-Lobato L, Rosiñol L, Marín P, Pedraza A, Martínez-Roca A, Carcelero E, Dolores Herrera M, Teresa Solano M, Ramos C, de Llobet N, Serrahima A, Lozano M, Cid J, Martínez C, Suárez-Lledó M, Urbano-Ispizua Á, Fernández-Avilés F

A reproducible and safe at-home allogeneic haematopoietic cell transplant program: first experience in Central and Southern Europe.

Bone Marrow Transplant. May 2020, 55 (5) 965-973. Epub 13 Ene 2020
In 2015, we implemented an at-home allogeneic haematopoietic cell transplant (allo-HCT) program. Between 2015 and 2018, 252 patients underwent allo-HCT; 41 patients underwent allo-HCT in the at-home program (46% myeloablative; 63% unrelated donor; 32% posttransplant cyclophosphamide), and these patients were compared with 39 in-patients; safety, capacity to release beds for other programs, and economic efficiency cost were evaluated. We observed a lower incidence of febrile neutropenia in the at-home group compared with that in the in-patient group (32% versus 90%; p < 0.0001), whereas the incidence of aspergillosis was similar among groups (at-home 1% versus in-patient 3%; p = 0.5). The at-home patients showed a lower incidence of 1-year severe graft-versus-host disease (GVHD; 10% versus 29%; p = 0.03). There were no differences in 1-year transplant-related mortality, relapse, or overall survival among groups. The re-admission rate in the at-home group was 7%. The at-home setting was less expensive (9087 €/transplant), and its implementation increased capacity by 10.5 allo-HCTs/year. Moreover, a chimeric antigen receptor T-cell program could be established without increasing beds. Thus, our at-home allo-HCT program may be a safe modality to reduce febrile neutropenia and acute GVHD, resulting in lower re-admission rates.
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Hajek R, Pour L, Ozcan M, Martin Sánchez J, García Sanz R, Anagnostopoulos A, Oriol A, Cascavilla N, Terjung A, Lee Y, Briso EM, Dobkowska E, Hauns B, Špička I

A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Eur. J. Haematol. May 2020, 104 (5) 435-442. Epub 7 Mar 2020
We evaluated ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who had received 1-3 prior therapies.
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Conley BA, Staudt L, Takebe N, Wheeler DA, Wang L, Cardenas MF, Korchina V, Zenklusen JC, McShane LM, Tricoli JV, Williams PM, Lubensky I, O'Sullivan-Coyne G, Kohn E, Little RF, White J, Malik S, Harris LN, Mann B, Weil C, Tarnuzzer R, Karlovich C, Rodgers B, Shankar L, Jacobs PM, Nolan T, Berryman SM, Gastier-Foster J, Bowen J, Leraas K, Shen H, Laird PW, Esteller M, Miller V, Johnson A, Edmondson EF, Giordano TJ, Kim B, Ivy SP

The Exceptional Responders Initiative: Feasibility of A National Cancer Institute Pilot Study.

J. Natl. Cancer Inst. 27 Abr 2020, . Epub 27 Abr 2020
Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.
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Mattesen TB, Rasmussen MH, Sandoval J, Ongen H, Árnadóttir SS, Gladov J, Martinez-Cardus A, Castro de Moura M, Madsen AH, Laurberg S, Dermitzakis ET, Esteller M, Andersen CL, Bramsen JB

MethCORR modelling of methylomes from formalin-fixed paraffin-embedded tissue enables characterization and prognostication of colorectal cancer.

Nat Commun 24 Abr 2020, 11 (1) 2025. Epub 24 Abr 2020
Transcriptional characterization and classification has potential to resolve the inter-tumor heterogeneity of colorectal cancer and improve patient management. Yet, robust transcriptional profiling is difficult using formalin-fixed, paraffin-embedded (FFPE) samples, which complicates testing in clinical and archival material. We present MethCORR, an approach that allows uniform molecular characterization and classification of fresh-frozen and FFPE samples. MethCORR identifies genome-wide correlations between RNA expression and DNA methylation in fresh-frozen samples. This information is used to infer gene expression information in FFPE samples from their methylation profiles. MethCORR is here applied to methylation profiles from 877 fresh-frozen/FFPE samples and comparative analysis identifies the same two subtypes in four independent cohorts. Furthermore, subtype-specific prognostic biomarkers that better predicts relapse-free survival (HR = 2.66, 95%CI [1.67-4.22], P value < 0.001 (log-rank test)) than UICC tumor, node, metastasis (TNM) staging and microsatellite instability status are identified and validated using DNA methylation-specific PCR. The MethCORR approach is general, and may be similarly successful for other cancer types.
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Kim-Wanner SZ, Assenov Y, Nair MB, Weichenhan D, Benner A, Becker N, Landwehr K, Kuner R, Sültmann H, Esteller M, Koch I, Lindner M, Meister M, Thomas M, Bieg M, Klingmueller U, Schlesner M, Warth A, Brors B, Seifried E, Bonig H, Plass C, Risch A, Muley T

Genome-wide DNA methylation profiling in early stage I lung adenocarcinoma reveals predictive aberrant methylation in the promoter region of the long non-coding RNA PLUT - an exploratory study.

J Thorac Oncol 6 Abr 2020, . Epub 6 Abr 2020
Surgery is the treatment of choice in early stage I lung adenocarcinoma. However, a considerable portion of patients experience recurrence within the first two years following complete resection. Especially suitable prognostic biomarkers are not available that identify patients at high risk for recurrence who may probably benefit from adjuvant treatment. This study aimed to identify methylation markers for early recurrence that may become important tools for the development of new treatment modalities.
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