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Laura Mondragón

Researchers at the Josep Carreras Institute will study a rare T-cell lymphoma thanks to the Leukemia Research Foundation

Dr. Laura Mondragón, “T-cell lymphoma” group leader at the Josep Carreras Leukaemia Research Institute, has been granted a new project to fight against angioimmunoblastic T cell lymphoma (AITL). The project, starting October 1st 2022, is funded by the Leukemia Research Foundation based in Northfield, Illinois (USA) and aims to exploit the latest generation of animal models for AITL, to better understand this type of adult lymphoma and open the door to new therapeutic approaches.

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Dr. Esteller & Dra. Pujol (IDIBELL)

Discovered epigenetic alterations associated with the COVID-19 related severe inflammatory syndrome in childhood

Researchers from the Cancer Epigenetics group led by Dr. Manel Esteller at the Josep Carreras Leukaemia Research Institute and Dr. Aurora Pujol, from the Bellvitge Biomedical Research Institute, have identified an epigenetic signature associated to the development of the Multisystem Inflammatory Syndrome in Children (MIS-C) after a SARS-CoV-2 virus infection. The signature has been named EPIMISC, in line with previous studies on the epigenetics of COVID-19 from the same team.

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David Corujo

Cancer vs. the immune system: macroH2A, a chromatin protein, can turn cancer cells deaf to immune commands

Researchers from the Buschbeck lab and IGTP are pushing forward our understanding of the role of the macroH2A histone variants in the progression of cancer and the crosstalk of cancer cells with the immune system. In a research paper recently published at the journal Cell Reports, the team identified two different areas where macroH2As can act when cancer cells are exposed to cytokines, the immune signaling machinery: chromatin regulation of gene expression and autocrine signaling secretion.

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Francesc Solé 2022

Genetic information from myelodysplastic syndromes’ patients incorporated in the latest update of the international standard risk assessment metric: the IPSS-M

Researchers from the Josep Carreras Leukaemia Research Institute, Dr. Francesc Solé and Dr. Laura Palomo from the Myelodysplastic Syndromes Group, and Dr. Lurdes Zamora from the Myeloid Neoplasms Group, participated in the international consortium that developed the new molecular-based prognostic index for Myelodysplastic Syndromes, the IPSS-M. This new tool, recently published at NEJM Evidence, a new journal from the New England Journal of Medicine Publishing Group, will allow a better risk stratification of patients and, thus, a better treatment, tailored to their individual needs.

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Graupera paper miransertib

A new fast and reliable experimental model for vascular malformations leads to the identification of miransertib as a promising therapy option

A team of researchers led by Dr. Sandra Castillo and Dr. Mariona Graupera, from the Josep Carreras Leukaemia Research Institute and member of the CIBERONC, have found the AKT inhibitor miransertib could be a new molecular treatment effective against low-flow vascular malformations, a long-awaited milestone. Their results, published at the journal EMBO Molecular Medicine, are based on a new in vivo model of blood vessels growth (angiogenesis) that could become the gold standard for this kind of studies in the short term.

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Manel Esteller & Alberto Bueno 2

A mechanism is found explaining how cancer cells turn into normal harmless ones

A new research​​ describes how highly proliferative leukemia cells end up becoming normal cells that no longer multiply, by changing the chemical modifications -the so-called epigenetics- of a type of its genetic material: the messenger RNA. The article, published in the high-impact journal Leukemia, is authored by Alberto Bueno-Costa, researcher at the group of Dr. Manel Esteller, supervisor of the research and Director of the Josep Carreras Leukaemia Research Institute, ICREA Researcher and Professor at the University of Barcelona.

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Damiana Álvarez-Errico

In vitro myelopoiesis from iPSCs resembles human early blood formation and opens the door to new therapeutic opportunities for cancer and inflammatory diseases

A team coordinated by the Wellcome Sanger Institute and the Josep Carreras Leukaemia Research Institute has generated a robust molecular map of the differentiation of human induced pluripotent stem cells (iPSC) into macrophages, which faithfully recapitulates the early stages of myeloid differentiation. This roadmap of early myeloid differentiation represents an essential step towards better understanding the initial stages of hematopoiesis, which are largely unexplored in humans, and will open up new cell-based therapeutic opportunities.

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Recent publications

Veronica Davalos, Carlos A. García-Prieto, Gerardo Ferrer, Sergio Aguilera-Albesa, Juan Valencia-Ramos, Agustí Rodríguez-Palmero, Montserrat Ruiz, Laura Planas-Serra, Iolanda Jordan, Iosune Alegría, Patricia Flores-P erez, Veronica Cantarín, Victoria Fumado, Maria Teresa Viadero, Carlos Rodrigo, Maria Méndez-Hernández, Eduardo Lopez-Granados, Roger Colobran, Jacques G. Riviere, Pere Soler-Palacín, Aurora Pujol, Manel Esteller

Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study

Lancet eClinicalMedicine 25 Jun 2022, 50 .
Background: Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C. Methods: Peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants. Findings: The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C. Interpretation: We have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder.
Ramos-Muntada M, Trincado JL, Blanco J, Bueno C, Rodríguez-Cortez VC, Bataller A, López-Millán B, Schwab C, Ortega M, Velasco P, Blanco ML, Nomdedeu J, Ramírez-Orellana M, Minguela A, Fuster JL, Cuatrecasas E, Camós M, Ballerini P, Escherich G, Boer J, denBoer M, Hernández-Rivas JM, Calasanz MJ, Cazzaniga G, Harrison CJ, Menéndez P, Molina O

Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high-hyperdiploid B-cell acute lymphoblastic leukemia

Molecular Oncology 21 Jun 2022, . Epub 21 Jun 2022
B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer. High hyperdiploidy (HHD) identifies the most frequent cytogenetic subgroup in childhood B-ALL. Although hyperdiploidy represents an important prognostic factor in childhood B-ALL, the specific chromosome gains with prognostic value in HHD-B-ALL remain controversial, and the current knowledge about the hierarchy of chromosome gains, clonal heterogeneity and chromosomal instability in HHD-B-ALL remains very limited. We applied automated sequential-iFISH coupled with single-cell computational modeling to identify the specific chromosomal gains of the eight typically gained chromosomes in a large cohort of 72 primary diagnostic (DX, n=62) and matched relapse (REL, n=10) samples from HHD-B-ALL patients with either favorable or unfavorable clinical outcome in order to characterize the clonal heterogeneity, specific chromosome gains and clonal evolution. Our data show a high degree of clonal heterogeneity and a hierarchical order of chromosome gains in DX samples of HHD-B-ALL. The rates of specific chromosome gains and clonal heterogeneity found in DX samples differ between HHD-B-ALL patients with favorable or unfavorable clinical outcome. In fact, our comprehensive analyses at DX using a computationally-defined risk predictor revealed low levels of trisomies +18+10 and low levels of clonal heterogeneity as robust relapse risk factors in minimal residual disease (MRD)-negative childhood HHD-B-ALL patients: relapse-free survival beyond 5-years: 22.1% vs 87.9%, P<0.0001 and 33.3% vs 80%, P<0.0001, respectively. Moreover, longitudinal analysis of matched DX-REL HHD-B-ALL samples revealed distinct patterns of clonal evolution at relapse. Our study offers a reliable prognostic sub-stratification of pediatric MRD-negative HHD-B-ALL patients.
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David Corujo, Roberto Malinverni, Juan Carrillo-Reixach, Oliver Meers, Arce Garcia-Jaraquemada, Marguerite-Marie Le Panne´rer, Vanesa Valero, Ainhoa Pérez, Álvaro Del Río-Álvarez, Laura Royo, Beatriz Pérez-González, Helena Raurell, Rafael D. Acemel, José M. Santos-Pereira, Marta Garrido-Pontnou, José Luis Gómez-Skarmeta, Lorenzo Pasquali, Josep Manyé, Carolina Armengol, Marcus Buschbeck

MacroH2As regulate enhancer-promoter contacts affecting enhancer activity and sensitivity to inflammatory cytokines

Cell Reports 21 Jun 2022, 39 (12) .
MacroH2A histone variants have a function in gene regulation that is poorly understood at the molecular level. We report that macroH2A1.2 and macroH2A2 modulate the transcriptional ground state of cancer cells and how they respond to inflammatory cytokines. Removal of macroH2A1.2 and macroH2A2 in hepatoblastoma cells affects the contact frequency of promoters and distal enhancers coinciding with changes in enhancer activity or preceding them in response to the cytokine tumor necrosis factor alpha. Although macroH2As regulate genes in both directions, they globally facilitate the nuclear factor κB (NF-κB)-mediated response. In contrast, macroH2As suppress the response to the pro-inflammatory cytokine interferon gamma. MacroH2A2 has a stronger contribution to gene repression than macroH2A1.2. Taken together, our results suggest that macroH2As have a role in regulating the response of cancer cells to inflammatory signals on the level of chromatin structure. This is likely relevant for the interaction of cancer cells with immune cells of their microenvironment.
Zhang YW, Mess J, Aizarani N, Mishra P, Johnson C, Romero-Mulero MC, Rettkowski J, Schönberger K, Obier N, Jäcklein K, Woessner NM, Lalioti ME, Velasco-Hernandez T, Sikora K, Wäsch R, Lehnertz B, Sauvageau G, Manke T, Menendez P, Walter SG, Minguet S, Laurenti E, Günther S, Grün D, Cabezas-Wallscheid N

Hyaluronic acid-GPRC5C signalling promotes dormancy in haematopoietic stem cells.

Nat Cell Biol 20 Jun 2022, . Epub 20 Jun 2022
Bone marrow haematopoietic stem cells (HSCs) are vital for lifelong maintenance of healthy haematopoiesis. In inbred mice housed in gnotobiotic facilities, the top of the haematopoietic hierarchy is occupied by dormant HSCs, which reversibly exit quiescence during stress. Whether HSC dormancy exists in humans remains debatable. Here, using single-cell RNA sequencing, we show a continuous landscape of highly purified human bone marrow HSCs displaying varying degrees of dormancy. We identify the orphan receptor GPRC5C, which enriches for dormant human HSCs. GPRC5C is also essential for HSC function, as demonstrated by genetic loss- and gain-of-function analyses. Through structural modelling and biochemical assays, we show that hyaluronic acid, a bone marrow extracellular matrix component, preserves dormancy through GPRC5C. We identify the hyaluronic acid-GPRC5C signalling axis controlling the state of dormancy in mouse and human HSCs.
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Estupiñán-Moreno E, Ortiz-Fernández L, Li T, Hernández-Rodríguez J, Ciudad L, Andrés-León E, Terron-Camero LC, Prieto-González S, Espígol-Frigolé G, Cid MC, Márquez A, Ballestar E, Martín J

Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids.

Ann Rheum Dis 15 Jun 2022, . Epub 15 Jun 2022
Giant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis.
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