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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Eduard Porta Entrevista

Eduard Porta: "The future of Artificial Intelligence in biomedicine is bright"

Dr. Eduard Porta, leader of the Cancer Immunogenomics group at the Josep Carreras Leukaemia Research Institute, has participated in a community initiative to put into context the value of AlphaFold2 predictions, an algorithm created by Deep Mind, the Google's specialized artificial intelligence company, capable of determining the three-dimensional structure of all known human proteins. Their conclusions have recently been published in the specialized journal Nature Structural Biology.

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Recent publications

Caillot M, Miloudi H, Taly A, Profitós-Pelejà N, Santos JC, Ribeiro ML, Maitre E, Saule S, Roué G, Jardin F, Sola B

Exportin 1-mediated nuclear/cytoplasmic trafficking controls drug sensitivity of classical Hodgkin lymphoma.

Molecular Oncology 2 Feb 2023, . Epub 2 Feb 2023
Exportin 1 (XPO1) is the main nuclear export receptor that controls the subcellular trafficking and the functions of major regulatory proteins. XPO1 is overexpressed in various cancers and small inhibitors of nuclear export (SINEs) have been developed to inhibit XPO1. In primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL), the XPO1 gene may be mutated on one nucleotide and encodes the mutant XPO1
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Calvete O, Mestre J, Durmaz A, Gurnari C, Maciejewski JP, Solé F

Are the current guidelines for identification of myelodysplastic syndrome with germline predisposition strong enough?

British Journal of Haematology 30 Jan 2023, . Epub 30 Jan 2023More information
David Cruz, Rocío Rodríguez-Romanos, Marta González-Bartulos, Irene García-Cadenas, Rafael de la Cámara, Inmaculada Heras, Ismael Buño, Nazly Santos, Natàlia Lloveras, Pilar Velarde, Esperanza Tuset, Carmen Martínez, Marcos González, Guillermo F. Sanz, Christelle Ferrá, Antonia Sampol, Rosa Coll, Jose A. Pérez-Simón, Javier López-Jiménez, Manuel Jurado, David Gallardo

LAG3 genotype of the donor and clinical outcome after allogeneic transplantation from HLA-identical sibling donors

Frontiers in Immunology 20 Jan 2023, 14 . Epub 20 Jan 2023
Introduction: The association of polymorphisms in molecules involved in the immune response (checkpoint inhibitors) with the clinical outcome after allogeneic transplantation (alloHSCT) has been described. Lymphocyte Activation 3 (LAG3) is a surface protein that plays a regulatory role in immunity as an inhibitory immune checkpoint molecule. Methods: To determine its role in the alloHSCT setting, we analyzed 797 patients transplanted from HLA-identical sibling donors. The LAG3 rs870849 C>T polymorphism was genotyped in donors. Results: We detected a higher incidence of severe acute GVHD in patients transplanted from donors with TT genotype (p: 0.047, HR 1.64; 95% CI 1.01 – 2.67). Overall survival (OS) was worse for patients transplanted from donors with the rs870849 CT/TT genotype (0.020; HR, 1.44; 95% CI 1.06 – 1.96), as well as disease-free survival (DFS) (p: 0.002; HR 1.58, 95%CI: 1.18 – 2.14) and transplant-related mortality (TRM) (p< 0.001; HR: 1.88, 95% CI 1.29 – 2.74). When combining the LAG3 rs870849 and the PDCD1 rs36084323 genotypes of the donor, three genetic groups were well defined, allowing a good stratification of the risk of acute GVHD, TRM, OS and DFS. Discussion: We conclude that the LAG3 genotype of the donor may be considered in donors’ selection. As this selection may be limited in the HLA-identical sibling donor scenario, further studies exploring the impact of LAG3 genotype of the donor in unrelated transplantation are warranted.
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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