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Dr. Javierre & Tomás-Daza, Rovirosa

A refined method to peer into cancer cells’ inner working unlocks a hallmark of cancer: the interactome

Researchers at the Josep Carreras Leukaemia Research Institute have developed a method to analyze long-range interactions in the DNA -the interactome- from a very low amount of starting material. The method, named liCHi-C, opens the door to study the interactome of patient-derived samples instead of in vitro models for the first time and help us understand how alterations in regulatory regions affect the inner working of cancer cells.

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Diego Sánchez & Néstor Tirado

Researchers from the Hospital 12 de Octubre and the Josep Carreras Institute create a cell therapy based on STAb cells for a type of leukemia with few treatment options

Researchers of the Hospital Universitario 12 de Octubre in Madrid and the Josep Carreras Leukaemia Research Institute have developed a cell therapy for a type of leukemia which currently has very few treatment options. The innovative STAb therapy has been developed thanks to funding from the Spanish Association Against Cancer (AECC).

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Manel Esteller & Verónica Dávalos

Epigenetics breaks into the clinical practice of cancer

Dr. Manel Esteller and Dr. Verónica Dávalos, researchers at the Josep Carreras Leukaemia Research Institute, describe in a new article the impact of epigenetics on cancer treatment and how it has become a crucial tool to improve early detection, predict disease progression and become a target for new treatments.

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Francesc Solé 2022

Gender plays a great role in the prognosis of Myelodysplastic Syndromes

An international team of researchers on Myelodysplastic Syndromes (MDS) has found that gender is an important factor in the progression of the disease with men showing a poorer prognosis mainly due to cardiovascular interactions of anemia with mild MDS and a worse and broader mutational landscape than women. The team proposes to incorporate sex and its associated distinctive features into the informed prognostic scoring system (IPSS), to better stratify MDS patients and improve personalized decision making in the clinic.

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Ballestar lab 2022

Researchers find epigenetic alterations in the immune system behind severe Covid-19

Monocytes from severe covid-19 patients show an altered epigenetic status, according to results by the Epigenetic and Immune Disease group of the Josep Carreras Leukaemia Research Institute. The alterations found in these cells, key in promoting inflammation, can explain features of the aberrant immune response against Sars-Cov-2 infection, such as impaired communication with other immune cells and maturation defects. This comprehensive analysis of monocyte’s epigenetics under severe covid-19, the first of its kind, stresses the importance of these cells in modulating the immune response.

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Recent publications

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 Jan 2023, 14 (1) 268. Epub 17 Jan 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 Jan 2023, e16554. Epub 4 Jan 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 Dec 2022, 14 (1) 188. Epub 28 Dec 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 Dec 2022, . Epub 13 Dec 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 Dec 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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