Publicació científica

S'han trobat 1721 publicacions amb els criteris indicats.
Ortiz-Barahona V, Soler M, Davalos V, García-Prieto CA, Janin M, Setien F, Fernández-Rebollo I, Bech-Serra JJ, De La Torre C, Guil S, Villanueva A, Zhang PH, Yang L, Guarnacci M, Schumann U, Preiss T, Balaseviciute U, Montal R, Llovet JM, Esteller M

Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer.

Molecular Cancer 12 Mai 2023, 22 (1) 83. Epub 12 Mai 2023
Background: RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. Methods: Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. Results: In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. Conclusion: The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability.
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Mohty M, Malard F, Alaskar AS, Aljurf M, Arat M, Bader P, Baron F, Bazarbachi A, Blaise D, Brissot E, Ciceri F, Corbacioglu S, Dalle JH, Dignan F, Huynh A, Kenyon M, Nagler A, Pagliuca A, Perić Z, Richardson PG, Ruggeri A, Ruutu T, Yakoub-Agha I, Duarte RF, Carreras E

Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a refined classification from the European society for blood and marrow transplantation (EBMT).

Bone Marrow Transplantation 24 Abr 2023, . Epub 24 Abr 2023
Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). A new definition for diagnosis, and a severity grading system for SOS/VOD in adult patients, was reported a few years ago on behalf of the European Society for Blood and Marrow Transplantation (EBMT). The aim of this work is to update knowledge regarding diagnosis and severity assessment of SOS/VOD in adult patients, and also its pathophysiology and treatment. In particular, we now propose to refine the previous classification and distinguish probable, clinical and proven SOS/VOD at diagnosis. We also provide an accurate definition of multiorgan dysfunction (MOD) for SOS/VOD severity grading based on Sequential Organ Failure Assessment (SOFA) score.
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Auñón C, Sanvisens A, Turon E, Vidal-Vila A, Puigdemont M, Osca-Gelis G, Eraso A, Marcos-Gragera R

Time trends and survival of marginal zone lymphoma over 25 years in Girona, Spain (1994-2018).

Cancer Medicine 19 Abr 2023, . Epub 19 Abr 2023
Objective: To analyze the incidence, incidence trends, and survival of marginal zone lymphomas (MZLs) in Girona and to describe these indicators based on the location in the case of extranodal MZLs. Methods: Population-based study of MZL collected in the Girona Cancer Registry, 1994-2018. Sociodemographic data, tumor location, and stage were obtained from clinical records. Crude (CR) and age-adjusted (ASRE ) incidence rates expressed per 100,000 person-years (p-y) were calculated. Joinpoint regression models were used for the trend analysis according to the MZL group. Five-year observed and net survival were analyzed. Results: A total of 472 MZLs were included, 44 (9.3%) were nodal, 288 (61.0%) extranodal, 122 (25.9%) splenic, and the rest (n = 18) MZL, NOS. The CR for the MZL was 2.89 × 100,000 p-y (95% CI: 2.63-3.15), the ASRE was 3.26 × 100,000 p-y (95% CI: 2.97-3.57), and the annual percentage change (APC) was 1.6 (95% CI: 0.5-2.7). The ASRE for nodal MZL was 0.30 × 100,000 p-y (95% CI: 0.22-0.41) and showed an APC of 2.9% (95% CI: -16.4-26.6). For extranodal MZL, the ASRE was 1.98 × 100,000 p-y (95% CI: 1.76-2.23) and the APC was -0.4 (95% CI: -2.0-1.2). The most frequent locations of this type of MZL were the gastric (35.4%), skin (13.2%), and respiratory system (11.8%). The ASRE of the splenic MZL was 0.85 (95% CI: 0.71-1.02) with an APC of 12.8 (95% CI: 2.5-24.0). The 5-year net survival of MZL was 82.1% (95% CI: 76.3-86.5). Conclusions: This study reveals differences in the incidence and trend of the incidence of MZL according to the subgroup, showing a significant increase in the overall MZL mainly due to splenic MZL type.
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Janin M, Esteller M

Global Shift in Alternative Splicing and Therapeutic Susceptibilities in Leukemia Driven by METTL3 Overexpression

Blood Cancer Discovery 17 Abr 2023, OF1-OF4. Epub 17 Abr 2023
Mutations in splicing factors are commonly observed in chronic lymphocytic leukemia (CLL); however, other mechanisms can also contribute to the dysregulation of alternative splicing. One example is the overexpression of the m6A RNA methyltransferase METTL3, that by depositing the epitranscriptomic mark in spliceosome transcripts leads to aberrant splicing, but at the same time creates vulnerability to METTL3 inhibitors. See related article by Wu et al., (8) .
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Meyer C, Larghero P, Almeida Lopes B, Burmeister T, Gröger D, Sutton R, Venn NC, Cazzaniga G, Corral Abascal L, Tsaur G, Fechina L, Emerenciano M, Pombo-de-Oliveira MS, Lund-Aho T, Lundán T, Montonen M, Juvonen V, Zuna J, Trka J, Ballerini P, Lapillonne H, Van der Velden VHJ, Sonneveld E, Delabesse E, de Matos RRC, Silva MLM, Bomken S, Katsibardi K, Keernik M, Grardel N, Mason J, Price R, Kim J, Eckert C, Lo Nigro L, Bueno C, Menendez P, Zur Stadt U, Gameiro P, Sedék L, Szczepański T, Bidet A, Marcu V, Shichrur K, Izraeli S, Madsen HO, Schäfer BW, Kubetzko S, Kim R, Clappier E, Trautmann H, Brüggemann M, Archer P, Hancock J, Alten J, Möricke A, Stanulla M, Lentes J, Bergmann AK, Strehl S, Köhrer S, Nebral K, Dworzak MN, Haas OA, Arfeuille C, Caye-Eude A, Cavé H, Marschalek R

The KMT2A recombinome of acute leukemias in 2023.

Leukemia 5 Abr 2023, . Epub 5 Abr 2023
Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.
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Alburquerque-Bejar JJ, Navajas-Chocarro P, Saigi M, Ferrero-Andres A, Morillas JM, Vilarrubi A, Gomez A, Mate JL, Munoz-Marmol AM, Romero OA, Blecua P, Davalos V, Esteller M, Pros E, Llabata P, Torres-Diz M, Esteve-Codina A, Sanchez-Cespedes M

MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer.

Cell Reports Medicine 5 Abr 2023, 101006. Epub 5 Abr 2023
Elucidating the adaptive mechanisms that prevent host immune response in cancer will help predict efficacy of anti-programmed death-1 (PD1)/L1 therapies. Here, we study the cell-intrinsic response of lung cancer (LC) to interferon-γ (IFNγ), a cytokine that promotes immunoresponse and modulates programmed death-ligand 1 (PD-L1) levels. We report complete refractoriness to IFNγ in a subset of LCs as a result of JAK2 or IFNGR1 inactivation. A submaximal response affects another subset that shows constitutive low levels of IFNγ-stimulated genes (IγSGs) coupled with decreased H3K27ac (histone 3 acetylation at lysine 27) deposition and promoter hypermethylation and reduced IFN regulatory factor 1 (IRF1) recruitment to the DNA on IFNγ stimulation. Most of these are neuroendocrine small cell LCs (SCLCs) with oncogenic MYC/MYCL1/MYCN. The oncogenic activation of MYC in SCLC cells downregulates JAK2 and impairs IγSGs stimulation by IFNγ. MYC amplification tends to associate with a worse response to anti-PD1/L1 therapies. Hence alterations affecting the JAK/STAT pathway and MYC activation prevent stimulation by IFNγ and may predict anti-PD1/L1 efficacy in LC.
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Veronica Davalos, Claudia D. Lovell, Richard Von Itter, Igor Dolgalev, Praveen Agrawal, Gillian Baptiste, David J. Kahler, Elena Sokolova, Sebastian Moran, Laia Piqué, Eleazar Vega-Saenz de Miera, Barbara Fontanals-Cirera, Alcida Karz, Aristotelis Tsirigos, Chi Yun, Farbod Darvishian, Heather C. Etchevers, Iman Osman, Manel Esteller, Markus Schober, Eva Hernando

An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma

Nat Commun . 2023 Apr 4;14(1):1867 4 Abr 2023, . Epub 4 Abr 2023
Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-to-mesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 - isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-binding domain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanoma progression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC-associated target genes. Our findings indicate that DNA methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.
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Sauta E, Robin M, Bersanelli M, Travaglino E, Meggendorfer M, Zhao LP, Caballero Berrocal JC, Sala C, Maggioni G, Bernardi M, Di Grazia C, Vago L, Rivoli G, Borin L, D'Amico S, Tentori CA, Ubezio M, Campagna A, Russo A, Mannina D, Lanino L, Chiusolo P, Giaccone L, Voso MT, Riva M, Oliva EN, Zampini M, Riva E, Nibourel O, Bicchieri M, Bolli N, Rambaldi A, Passamonti F, Savevski V, Santoro A, Germing U, Kordasti S, Santini V, Diez-Campelo M, Sanz G, Sole F, Kern W, Platzbecker U, Ades L, Fenaux P, Haferlach T, Castellani G, Della Porta MG

Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

Journal of Clinical Oncology 17 Mar 2023, JCO2201784. Epub 17 Mar 2023
Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M.
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Noguera-Castells A, García-Prieto CA, Álvarez-Errico D, Esteller M

Validation of the new EPIC DNA methylation microarray (900K EPIC v2) for high-throughput profiling of the human DNA methylome.

Epigenetics 5 Mar 2023, 18 (1) 2185742.
DNA methylation, one of the best characterized epigenetic marks in the human genome, plays a pivotal role in gene transcription regulation and other biological processes in humans. On top of that, the DNA methylome undergoes profound changes in cancer and other disorders. However, large-scale and population-based studies are limited by high costs and the need for considerable expertise in data analysis for whole-genome bisulphite-sequencing methodologies. Following the success of the EPIC DNA methylation microarray, the newly developed Infinium HumanMethylationEPIC version 2.0 (900K EPIC v2) is now available. This new array contains more than 900,000 CpG probes covering the human genome and excluding masked probes from the previous version. The 900K EPIC v2 microarray adds more than 200,000 probes covering extra DNA cis-regulatory regions such as enhancers, super-enhancers and CTCF binding regions. Herein, we have technically and biologically validated the new methylation array to show its high reproducibility and consistency among technical replicates and with DNA extracted from FFPE tissue. In addition, we have hybridized primary normal and tumoural tissues and cancer cell lines from different sources and tested the robustness of the 900K EPIC v2 microarray when analysing the different DNA methylation profiles. The validation highlights the improvements offered by the new array and demonstrates the versatility of this updated tool for characterizing the DNA methylome in human health and disease.
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O. Calvete, J. Mestre, A. Jerez, F. Solé, None

The Secondary Myelodysplastic Neoplasms (MDS) Jigsaw

Cancers 26 Feb 2023, . Epub 26 Feb 2023
There is a great deal of controversy in the hematologic community regarding the classification of secondary myelodysplastic neoplasms (MDSs). Current classifications are based on the presence of genetic predisposition and MDS post-cytotoxic therapy (MDS-pCT) etiologies. However, since these risk factors are not exclusive for secondary MDSs and there are multiple overlapping scenarios, a comprehensive and definitive classification is yet to come. In addition, a sporadic MDS might arise after a primary tumor fulfills the diagnostic criteria of MDS-pCT without a causative cytotoxicity. In this review, we describe the triggering pieces of a secondary MDS jigsaw: previous cytotoxic therapy, germline predisposition and clonal hematopoiesis. Epidemiological and translational efforts are needed to put these pieces together and ascertain the real weight of each of these pieces in each MDS patient. Future classifications must contribute to understanding the role of secondary MDS jigsaw pieces in different concomitant or independent clinical scenarios associated with the primary tumor.