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 Oncology2 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
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 Haematology30 Gen 2023, . Epub 30 Gen 2023Més informació
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 Immunology20 Gen 2023, 14 . Epub 20 Gen 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 Commununications17 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.
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 Medecine4 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.
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 Epigenetics28 Des 2022, 14(1)188. Epub 28 Des 2022
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).
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.
Our results support the use of cfDNA methylation profiling as a rational approach to seeking non-invasive and reproducible epilepsy biomarkers.
CA: A Cancer Journal for Clinicians13 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 CancerDes 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.
Godoy-Tena G, Barmada A, Morante-Palacios O, de la Calle-Fabregat C, Martins-Ferreira R, Ferreté-Bonastre AG, Ciudad L, Ruiz-Sanmartín A, Martínez-Gallo M, Ferrer R, Ruiz-Rodriguez JC, Rodríguez-Ubreva J, Vento-Tormo R, Ballestar E
Epigenetic and transcriptomic reprogramming in monocytes of severe COVID-19 patients reflects alterations in myeloid differentiation and the influence of inflammatory cytokines.
Genome Med29 Nov 2022, 14(1)134. Epub 29 Nov 2022
COVID-19 manifests with a wide spectrum of clinical phenotypes, ranging from asymptomatic and mild to severe and critical. Severe and critical COVID-19 patients are characterized by marked changes in the myeloid compartment, especially monocytes. However, little is known about the epigenetic alterations that occur in these cells during hyperinflammatory responses in severe COVID-19 patients.
Giulia Maggioni, Matteo Bersanelli, Erica Travaglino, Ana Alfonso Piérola, Annika Kasprzak, Arnan Sangerman Montserrat, Elisabetta Sauta, Claudia Sala, Tommaso Matteuzzi, Manja Meggendorfer, Matteo Gnocchi, Lin-Pierre Zhao, Cristina Astrid Tentori, Kathrin Nachtkamp, Daniele Dall'Olio, Ettore Mosca, Marta Ubezio, Alessia Campagna, Antonio Russo, Giulia Rivoli, Massimo Bernardi, Lorenza Borin, Maria Teresa Voso, Marta Riva, Esther Natalie Oliva, Matteo Zampini, Elena Riva, Elena Saba, Saverio D'Amico, Luca Lanino, Benedetta Tinterri, Francesca Re, Marilena Bicchieri, Laura Giordano, Giovanni Angelotti, Pierandrea Morandini, Anne Sophie Kubasch, Francesco Passamonti, Alessandro Rambaldi, Victor Savevski, Armando Santoro, Arjan A van de Loosdrecht, Alice Brogi, Valeria Santini, Shahram Kordasti, Guillermo Sanz, Francesc Sole, Norbert Gattermann, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Ulrich Germing, Maria Diez-Campelo, Matteo G Della Porta.
A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes: a multicentre, observational cohort study.
The Lancet Haematology24 Nov 2022, . Epub 24 Nov 2022
Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality.