Research publications

Found 1427 publicacions matching the indicated search criteria.
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.
Comes M, Batlle M, Ribera JM

Treatment adapted to pregnancy in a patient with Burkitt lymphoma.

Med Clin (Barc) 12 Jun 2020, 154 (11) 470-471. Epub 20 Jul 2019More information
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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Stik G, Vidal E, Barrero M, Cuartero S, Vila-Casadesús M, Mendieta-Esteban J, Tian TV, Choi J, Berenguer C, Abad A, Borsari B, le Dily F, Cramer P, Marti-Renom MA, Stadhouders R, Graf T

CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.

Nat. Genet. 8 Jun 2020, . Epub 8 Jun 2020
Three-dimensional organization of the genome is important for transcriptional regulation
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Casas E, Vavouri T

Mechanisms of epigenetic inheritance of variable traits through the germline.

Reproduction Jun 2020, 159 (6) R251-R263. Epub 22 Apr 2020
During the past half century, evidence for inheritance of variable traits has accumulated from experiments in plants and animals and epidemiological studies in humans. Here, we summarize some of the reported cases of epigenetic inheritance and the proposed mechanisms involved in the transmission of non-genetic information between generations in plants, nematodes, flies and mammals. It has long been accepted that information is epigenetically inherited in plants. Although many questions regarding the underlying mechanisms remain to be answered, it is now evident that epigenetic mechanisms are also responsible for the transmission of phenotypes in animals. We highlight similarities and differences between models and species.
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Blasco M, Martínez-Roca A, Rodríguez-Lobato LG, Garcia-Herrera A, Rosiñol L, Castro P, Fernández S, Quintana LF, Cibeira MT, Bladé J, Fernández de Larrea C, Tovar N, Jimenez R, Poch E, Guillen E, Campistol JM, Carreras E, Diaz-Ricart M, Palomo M

Complement as the enabler of carfilzomib-induced thrombotic microangiopathy.

Br. J. Haematol. 29 May 2020, . Epub 29 May 2020
Carfilzomib has been associated with the development of thrombotic microangiopathy (TMA) in relapsed/refractory multiple myeloma patients, a severe disease with no currently available aetiological treatment. We evaluated the potential role of terminal complement pathway in four patients with carfilzomib-induced TMA. Membrane attack complex (C5b-9) deposition on endothelial cells in culture exposed to plasma from patients during the acute phase of the disease suggests complement overactivation as a mechanism of potential endothelial damage in three out of four patients. If confirmed in larger cohorts, C5b-9 evaluation will allow early identification of patients who could benefit from complement blockade and treatment monitoring.
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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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Colli ML, Ramos-Rodríguez M, Nakayasu ES, Alvelos MI, Lopes M, Hill JLE, Turatsinze JV, Coomans de Brachène A, Russell MA, Raurell-Vila H, Castela A, Juan-Mateu J, Webb-Robertson BM, Krogvold L, Dahl-Jorgensen K, Marselli L, Marchetti P, Richardson SJ, Morgan NG, Metz TO, Pasquali L, Eizirik DL

An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells.

Nat Commun 22 May 2020, 11 (1) 2584. Epub 22 May 2020
Interferon-α (IFNα), a type I interferon, is expressed in the islets of type 1 diabetic individuals, and its expression and signaling are regulated by T1D genetic risk variants and viral infections associated with T1D. We presently characterize human beta cell responses to IFNα by combining ATAC-seq, RNA-seq and proteomics assays. The initial response to IFNα is characterized by chromatin remodeling, followed by changes in transcriptional and translational regulation. IFNα induces changes in alternative splicing (AS) and first exon usage, increasing the diversity of transcripts expressed by the beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may expand antigens presented by beta cells to the immune system. Beta cells also up-regulate the checkpoint proteins PDL1 and HLA-E that may exert a protective role against the autoimmune assault. Data mining of the present multi-omics analysis identifies two compound classes that antagonize IFNα effects on human beta cells.
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Laporte-Amargos J, Gudiol C, Arnan M, Puerta-Alcalde P, Carmona-Torre F, Huguet M, Albasanz-Puig A, Parody R, Garcia-Vidal C, Del Pozo JL, Batlle M, Tebé C, Rigo-Bonnin R, Muñoz C, Padullés A, Tubau F, Videla S, Sureda A, Carratalà J

Efficacy of extended infusion of β-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE).

Trials 18 May 2020, 21 (1) 412. Epub 18 May 2020
Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal β-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN.
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Im A, Rashidi A, Wang T, Hemmer M, MacMillan ML, Pidala J, Jagasia M, Pavletic S, Majhail NS, Weisdorf D, Abdel-Azim H, Agrawal V, Al-Homsi AS, Aljurf M, Askar M, Auletta JJ, Bashey A, Beitinjaneh A, Bhatt VR, Byrne M, Cahn JY, Cairo M, Castillo P, Cerny J, Chhabra S, Choe H, Ciurea S, Daly A, Perez MAD, Farhadfar N, Gadalla SM, Gale R, Ganguly S, Gergis U, Hanna R, Hematti P, Herzig R, Hildebrandt GC, Lad DP, Lee C, Lehmann L, Lekakis L, Kamble RT, Kharfan-Dabaja MA, Khandelwal P, Martino R, Murthy HS, Nishihori T, O'Brien TA, Olsson RF, Patel SS, Perales MA, Prestidge T, Qayed M, Romee R, Schoemans H, Seo S, Sharma A, Solh M, Strair R, Teshima T, Urbano-Ispizua A, Van der Poel M, Vij R, Wagner JL, William B, Wirk B, Yared JA, Spellman SR, Arora M, Hamilton BK

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Biol. Blood Marrow Transplant. 17 May 2020, . Epub 17 May 2020
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with relatively low incidence of GVHD. Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haploHCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (2013-2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced intensity (RIC) conditioning and bone marrow (BM) or peripheral blood (PB) graft source. 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2-4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (p=0.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (p<0.001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2-4 acute GVHD; however, older donor age (30-49 versus <29 years) was significantly associated with higher rates of grade 2-4 acute GVHD (HR 1.53, 95% CI 1.11-2.12, p=0.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR 1.70, 95% CI 1.11-2.62, p=0.01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haploHCT.  Our results indicate that in RIC haploHCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
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