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Dr. Javierre & Tomás-Daza, Rovirosa

Un mètode optimitzat per observar el funcionament intern de les cèl·lules canceroses desbloqueja una fita en la lluita contra el càncer: l'interactoma

Investigadors de l'Institut de Recerca contra la Leucèmia Josep Carreras han desenvolupat un mètode per analitzar interaccions de llarg abast a l'ADN -l'interactoma- a partir d'una quantitat molt baixa de material de partida. El mètode, anomenat liCHi-C, obre la porta a estudiar l'interactoma de mostres obtingudes directament de pacients per primera vegada, en lloc de models in vitro, i ens ajuda a comprendre com les alteracions a les regions reguladores afecten el funcionament intern de les cèl·lules canceroses.

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Diego Sánchez & Néstor Tirado

Investigadors de l'Hospital 12 de Octubre i l'Institut Josep Carreras creen una teràpia cel·lular basada en l'ús de cèl·lules punyal per fer front a una mena de leucèmia amb escasses opcions de tractament

Investigadors de l'Hospital Universitari 12 de Octubre de Madrid i de l'Institut de Recerca contra la Leucèmia Josep Carreras han creat una teràpia cel·lular per una mena de leucèmia que en l'actualitat compta amb molt poques alternatives de tractament. La innovadora teràpia, anomenada STAb, ha estat desenvolupada gràcies al finançament aportat per l’Associació Espanyola Contra el Càncer (AECC).

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Manel Esteller & Verónica Dávalos

L'epigenètica irromp a la pràctica clínica del càncer

El Dr. Manel Esteller i la Dra. Verónica Dávalos, investigadors de l’Institut de Recerca contra la Leucèmia Josep Carreras, descriuen en un nou article l’impacte de l’epigenètica en el tractament contra el càncer i com ha esdevingut una eina indispensable per millorar la detecció precoç, predir l'evolució de la malaltia i convertir-se en una diana de tractaments nous.

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8 IJC Elsevier

Vuit investigadors de l’Institut Josep Carreras reconeguts per Elsevier entre els més rellevants internacionalment

Manel Esteller, Josep Maria Ribera, Esteban Ballestar, Alejandro Vaquero, Montse Sanchez-Cespedes, María Berdasco, Fumiichiro Yamamoto i Ciril Rozman, juntament amb una vintena d’investigadors i personal mèdic d’institucions del Campus Can Ruti, són inclosos al llistat Scopus d’Elsevier, que recull els 200 mil investigadors i investigadores més reconeguts a nivell global.

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Francesc Solé 2022

El gènere juga un paper important en el pronòstic de les Síndromes Mielodisplàstiques

Un equip internacional d'investigadors sobre Síndromes Mielodisplàstiques (SMD) ha descobert que el gènere és un factor important en la progressió de la malaltia. Segons l'estudi, els homes mostren un pitjor pronòstic, principalment per les interaccions cardiovasculars de l'anèmia amb SMD lleus i un panorama mutacional pitjor i més ampli que el de les dones. L'equip proposa incorporar el sexe i les seves característiques distintives associades al sistema estàndard de puntuació de pronòstic (IPSS), per estratificar millor els pacients amb SMD i millorar la presa de decisions personalitzada a la clínica.

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Ballestar lab 2022

Investigadors troben alteracions epigenètiques al sistema immunitari darrere de la COVID-19 greu

Els monòcits de pacients de covid-19 severa mostren un estat epigenètic alterat, segons els resultats del grup d'Epigenètica i Malalties Immunitàries de l'Institut de Recerca contra la Leucèmia Josep Carreras. Les alteracions trobades en aquestes cèl·lules, clau en la promoció de la inflamació, poden explicar les característiques de la resposta immune aberrant contra la infecció per Sars-Cov-2, com la comunicació deficient amb altres cèl·lules immunitàries i els defectes de maduració. Aquesta anàlisi exhaustiva de l'epigenètica dels monòcits en covid-19 severa, la primera d'aquest tipus, posa en relleu la importància d'aquestes cèl·lules en la modulació de la resposta immune.

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Últimes publicacions

Tomás-Daza L, Rovirosa L, López-Martí P, Nieto-Aliseda A, Serra F, Planas-Riverola A, Molina O, McDonald R, Ghevaert C, Cuatrecasas E, Costa D, Camós M, Bueno C, Menéndez P, Valencia A, Javierre BM

Low input capture Hi-C (liCHi-C) identifies promoter-enhancer interactions at high-resolution.

Nature Commununications 17 Gen 2023, 14 (1) 268. Epub 17 Gen 2023
Long-range interactions between regulatory elements and promoters are key in gene transcriptional control; however, their study requires large amounts of starting material, which is not compatible with clinical scenarios nor the study of rare cell populations. Here we introduce low input capture Hi-C (liCHi-C) as a cost-effective, flexible method to map and robustly compare promoter interactomes at high resolution. As proof of its broad applicability, we implement liCHi-C to study normal and malignant human hematopoietic hierarchy in clinical samples. We demonstrate that the dynamic promoter architecture identifies developmental trajectories and orchestrates transcriptional transitions during cell-state commitment. Moreover, liCHi-C enables the identification of disease-relevant cell types, genes and pathways potentially deregulated by non-coding alterations at distal regulatory elements. Finally, we show that liCHi-C can be harnessed to uncover genome-wide structural variants, resolve their breakpoints and infer their pathogenic effects. Collectively, our optimized liCHi-C method expands the study of 3D chromatin organization to unique, low-abundance cell populations, and offers an opportunity to uncover factors and regulatory networks involved in disease pathogenesis.
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García-Hernández V, Arambilet D, Guillén Y, Lobo-Jarne T, Maqueda M, Gekas C, González J, Iglesias A, Vega-García N, Sentís I, Trincado JL, Márquez-López I, Heyn H, Camós M, Espinosa L, Bigas A

β-Catenin activity induces an RNA biosynthesis program promoting therapy resistance in T-cell acute lymphoblastic leukemia.

EMBO Molecular Medecine 4 Gen 2023, e16554. Epub 4 Gen 2023
Understanding the molecular mechanisms that contribute to the appearance of chemotherapy resistant cell populations is necessary to improve cancer treatment. We have now investigated the role of β-catenin/CTNNB1 in the evolution of T-cell Acute Lymphoblastic Leukemia (T-ALL) patients and its involvement in therapy resistance. We have identified a specific gene signature that is directly regulated by β-catenin, TCF/LEF factors and ZBTB33/Kaiso in T-ALL cell lines, which is highly and significantly represented in five out of six refractory patients from a cohort of 40 children with T-ALL. By subsequent refinement of this gene signature, we found that a subset of β-catenin target genes involved with RNA-processing function are sufficient to segregate T-ALL refractory patients in three independent cohorts. We demonstrate the implication of β-catenin in RNA and protein synthesis in T-ALL and provide in vitro and in vivo experimental evidence that β-catenin is crucial for the cellular response to chemotherapy, mainly in the cellular recovery phase after treatment. We propose that combination treatments involving chemotherapy plus β-catenin inhibitors will enhance chemotherapy response and prevent disease relapse in T-ALL patients.
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Martins-Ferreira R, Leal B, Chaves J, Ciudad L, Samões R, Martins da Silva A, Pinho Costa P, Ballestar E

Circulating cell-free DNA methylation mirrors alterations in cerebral patterns in epilepsy.

Clin Epigenetics 28 Des 2022, 14 (1) 188. Epub 28 Des 2022
Background DNA methylation profiling of circulating cell-free DNA (cfDNA) has rapidly become a promising strategy for biomarker identification and development. The cell-type-specific nature of DNA methylation patterns and the direct relationship between cfDNA and apoptosis can potentially be used non-invasively to predict local alterations. In addition, direct detection of altered DNA methylation patterns performs well as a biomarker. In a previous study, we demonstrated marked DNA methylation alterations in brain tissue from patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Results We performed DNA methylation profiling in cfDNA isolated from the serum of MTLE patients and healthy controls using BeadChip arrays followed by systematic bioinformatic analysis including deconvolution analysis and integration with DNase accessibility data sets. Differential cfDNA methylation analysis showed an overrepresentation of gene ontology terms and transcription factors related to central nervous system function and regulation. Deconvolution analysis of the DNA methylation data sets ruled out the possibility that the observed differences were due to changes in the proportional contribution of cortical neurons in cfDNA. Moreover, we found no overrepresentation of neuron- or glia-specific patterns in the described cfDNA methylation patterns. However, the MTLE–HS cfDNA methylation patterns featured a significant overrepresentation of the epileptic DNA methylation alterations previously observed in the hippocampus. Conclusions Our results support the use of cfDNA methylation profiling as a rational approach to seeking non-invasive and reproducible epilepsy biomarkers.
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Veronica Davalos, Manel Esteller

Cancer epigenetics in clinical practice

CA: A Cancer Journal for Clinicians 13 Des 2022, . Epub 13 Des 2022
Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome. Whereas genetic changes disrupt the DNA sequence, epigenetic alterations contribute to the acquisition of hallmark tumor capabilities by regulating gene expression programs that promote tumorigenesis. Shifts in DNA methylation and histone mark patterns, the two main epigenetic modifications, orchestrate tumor progression and metastasis. These cancer-specific events have been exploited as useful tools for diagnosis, monitoring, and treatment choice to aid clinical decision making. Moreover, the reversibility of epigenetic modifications, in contrast to the irreversibility of genetic changes, has made the epigenetic machinery an attractive target for drug development. This review summarizes the most advanced applications of epigenetic biomarkers and epigenetic drugs in the clinical setting, highlighting commercially available DNA methylation-based assays and epigenetic drugs already approved by the US Food and Drug Administration.
Jiménez-Reinoso A, Tirado N, Martinez-Moreno A, Díaz VM, García-Peydró M, Hangiu O, Díez-Alonso L, Albitre Á, Penela P, Toribio ML, Menéndez P, Álvarez-Vallina L, Sánchez Martínez D

Efficient preclinical treatment of cortical T cell acute lymphoblastic leukemia with T lymphocytes secreting anti-CD1a T cell engagers.

J Immunother Cancer Des 2022, 10 (12) .
Background: The dismal clinical outcome of relapsed/refractory (R/R) T cell acute lymphoblastic leukemia (T-ALL) highlights the need for innovative targeted therapies. Although chimeric antigen receptor (CAR)-engineered T cells have revolutionized the treatment of B cell malignancies, their clinical implementation in T-ALL is in its infancy. CD1a represents a safe target for cortical T-ALL (coT-ALL) patients, and fratricide-resistant CD1a-directed CAR T cells have been preclinically validated as an immunotherapeutic strategy for R/R coT-ALL. Nonetheless, T-ALL relapses are commonly very aggressive and hyperleukocytic, posing a challenge to recover sufficient non-leukemic effector T cells from leukapheresis in R/R T-ALL patients. Methods: We carried out a comprehensive study using robust in vitro and in vivo assays comparing the efficacy of engineered T cells either expressing a second-generation CD1a-CAR or secreting CD1a x CD3 T cell-engaging Antibodies (CD1a-STAb). Results: We show that CD1a-T cell engagers bind to cell surface expressed CD1a and CD3 and induce specific T cell activation. Recruitment of bystander T cells endows CD1a-STAbs with an enhanced in vitro cytotoxicity than CD1a-CAR T cells at lower effector:target ratios. CD1a-STAb T cells are as effective as CD1a-CAR T cells in cutting-edge in vivo T-ALL patient-derived xenograft models. Conclusions: Our data suggest that CD1a-STAb T cells could be an alternative to CD1a-CAR T cells in coT-ALL patients with aggressive and hyperleukocytic relapses with limited numbers of non-leukemic effector T cells.
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