Blecua P, Davalos V, de Villasante I, Merkel A, Musulen E, Coll-SanMartin L, Esteller M
Refinement of computational identification of somatic copy number alterations using DNA methylation microarrays illustrated in cancers of unknown primary.
Brief Bioinform6 May 2022, . Epub 6 May 2022
High-throughput genomic technologies are increasingly used in personalized cancer medicine. However, computational tools to maximize the use of scarce tissues combining distinct molecular layers are needed. Here we present a refined strategy, based on the R-package 'conumee', to better predict somatic copy number alterations (SCNA) from deoxyribonucleic acid (DNA) methylation arrays. Our approach, termed hereafter as 'conumee-KCN', improves SCNA prediction by incorporating tumor purity and dynamic thresholding. We trained our algorithm using paired DNA methylation and SNP Array 6.0 data from The Cancer Genome Atlas samples and confirmed its performance in cancer cell lines. Most importantly, the application of our approach in cancers of unknown primary identified amplified potentially actionable targets that were experimentally validated by Fluorescence in situ hybridization and immunostaining, reaching 100% specificity and 93.3% sensitivity.
Garcia-Prieto CA, Martínez-Jiménez F, Valencia A, Porta-Pardo E
Detection of oncogenic and clinically actionable mutations in cancer genomes critically depends on variant calling tools.
Bioinformatics5 May 2022, . Epub 5 May 2022
The analysis of cancer genomes provides fundamental information about its aetiology, the processes driving cell transformation or potential treatments. While researchers and clinicians are often only interested in the identification of oncogenic mutations, actionable variants or mutational signatures, the first crucial step in the analysis of any tumor genome is the identification of somatic variants in cancer cells (i.e., those that have been acquired during their evolution). For that purpose, a wide range of computational tools have been developed in recent years to detect somatic mutations in sequencing data from tumor samples. While there have been some efforts to benchmark somatic variant calling tools and strategies, the extent to which variant calling decisions impact the results of downstream analyses of tumor genomes remains unknown.
Arribas AJ, Napoli S, Cascione L, Sartori G, Barnabei L, Gaudio E, Tarantelli C, Mensah AA, Spriano F, Zucchetto A, Rossi FM, Rinaldi A, De Moura MC, Jovic S, Bordone-Pittau R, Di Veroli A, Stathis A, Cruciani G, Stussi G, Gattei V, Brown JR, Esteller M, Zucca E, Rossi D, Bertoni F
Resistance to PI3κδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis.
Haematologica28 Apr 2022, . Epub 28 Apr 2022
PI3KPPinhibitors are active in patients with lymphoid neoplasms and a first series of them have been approved for the treatment of multiple types of B-cell lymphoid tumors, including marginal zone lymphoma (MZL). The identification of the mechanisms underlying either primary or secondary resistance is fundamental to optimize the use of novel drugs. Here, we present a model of secondary resistance to PI3Kffinhibitors obtained by prolonged exposure of a splenic MZL cell line to idelalisib. The VL51 cell line was kept under continuous exposure to idelalisib. The study included detailed characterization of the model, pharmacological screens, silencing experiments, validation experiments on multiple cell lines and on clinical specimens. VL51 developed resistance to idelalisib, copanlisib, duvelisib, and umbralisib. An integrative analysis of transcriptome and methylation underlined an enrichment of up-regulated transcripts and lowmethylated promoters in resistant cells, including IL-6/STAT3 and PDGFRA related genes and surface CD19 expression, alongside the repression of the let-7 family miRNAs, of miR-125, miR-130, miR-193 and miR-20. The use of the IL-6R blocking antibody tocilizumab, the STAT3 inhibitor stattic, the LIN28 inhibitor LIN1632, the PDGFR inhibitor masitinib and the anti-CD19 antibody drug conjugate loncastuximab tesirine were active compounds in the resistant cells as single agents and/or in combination with PI3K//inhibition. Findings were validated on additional in vitro lymphoma models and on clinical specimens. A novel model of resistance obtained from splenic MZL allowed the identification of therapeutic approaches able to improve the anti-tumor activity of PI3Kttinhibitors in B-cell lymphoid tumors.
Chronological age is a risk factor for SARS-CoV-2 infection and severe COVID-19. Previous findings indicate that epigenetic age could be altered in viral infection. However, the epigenetic aging in COVID-19 has not been well studied. In this study, DNA methylation of the blood samples from 232 healthy individuals and 413 COVID-19 patients is profiled using EPIC methylation array. Epigenetic ages of each individual are determined by applying epigenetic clocks and telomere length estimator to the methylation profile of the individual. Epigenetic age acceleration is calculated and compared between groups. We observe strong correlations between the epigenetic clocks and individual's chronological age (r > 0.8, p < 0.0001). We also find the increasing acceleration of epigenetic aging and telomere attrition in the sequential blood samples from healthy individuals and infected patients developing non-severe and severe COVID-19. In addition, the longitudinal DNA methylation profiling analysis find that the accumulation of epigenetic aging from COVID-19 syndrome could be partly reversed at late clinic phases in some patients. In conclusion, accelerated epigenetic aging is associated with the risk of SARS-CoV-2 infection and developing severe COVID-19. In addition, the accumulation of epigenetic aging from COVID-19 may contribute to the post-COVID-19 syndrome among survivors.
Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer.
J Natl Cancer Inst19 Apr 2022, . Epub 19 Apr 2022
Adoptive cell therapy (ACT) constitutes a major breakthrough in cancer management that has expanded in the past years due to impressive results showing durable and even curative responses for some patients with hematological malignancies. ACT leverages antigen specificity and cytotoxic mechanisms of the immune system, particularly relying on the patient´s T lymphocytes to target and eliminate malignant cells. This personalized therapeutic approach exemplifies the success of the joint effort of basic, translational and clinical researchers that has turned the patient´s immune system into a great ally in the search for a cancer cure. Adoptive cell therapies are constantly improving to reach a maximum beneficial clinical response. Despite being very promising therapeutic options for certain types of cancers, mainly melanoma and hematological malignancies, these individualized treatments still present several shortcomings including elevated costs, technical challenges, management of adverse side effects and a limited population of responder patients. Thus, it is crucial to discover and develop reliable and robust biomarkers to specifically and sensitively pinpoint the patients that will benefit the most from ACT, as well as those that are at higher risk of developing potentially serious toxicities. Although unique readouts of infused cell therapy success have not yet been identified, certain characteristics from the adoptive cells, the tumor and/or the tumor microenvironment have been recognized to predict patients' outcome upon ACT. Here, we comment on the importance of biomarkers to predict ACT chances of success to maximize efficacy of treatments and increase patients' survival.
The replacement of replication-coupled histones with non-canonical histone variants provides chromatin with additional properties and contributes to the plasticity of the epigenome. MacroH2A histone variants are counterparts of the replication-coupled histone H2A. They are characterized by a unique tripartite structure, consisting of a histone fold, an unstructured linker, and a globular macrodomain. MacroH2A1.1 and macroH2A1.2 are the result of alternative splicing of the MACROH2A1 gene and can have opposing biological functions. Here, we discuss the structural differences between the macrodomains of the two isoforms, resulting in differential ligand binding. We further discuss how this modulates gene regulation by the two isoforms, in cases resulting in opposing role of macroH2A1.1 and macroH2A1.2 in development and differentiation. Finally, we share recent insight in the evolution of macroH2As. Taken together, in this review, we aim to discuss in unprecedented detail distinct properties and functions of the fascinating macroH2A1 splice isoforms.
A wide range of immature acute leukemias (AL), ranging from acute myeloid leukemias with minimal differentiation to acute leukemias with an ambiguous lineage, i.e., acute undifferentiated leukemias and mixed phenotype acute leukemia with T- or B-plus myeloid markers, cannot be definitely assigned to a single cell lineage. This somewhat “grey zone” of AL expresses partly overlapping features with the most immature forms of T-cell acute lymphoblastic leukemia (T-ALL), i.e., early T-cell precursor ALL (ETP-ALL), near-ETP-ALL, and pro-T ALL. These are troublesome cases in terms of precise diagnosis because of their similarities and overlapping phenotypic features. Moreover, it has become evident that they share several genomic alterations, raising the question of how their phenotypes reflect distinct AL entities. The aim of this review was to provide a systematic overview of the genetic events associated with immature T-ALL and outline their relationship with treatment choices and outcomes, especially looking at the most recent preclinical and clinical studies. We wish to offer a basis for using the genetic information for new diagnostic algorithms, in order to better stratify patients and improve their management with more efficient and personalized therapeutic options. Understanding the genetic profile of this high-risk T-ALL subset is a prerequisite for changing the current clinical scenario.
Fernández-Simón E, Suárez-Calvet X, Carrasco-Rozas A, Piñol-Jurado P, López-Fernández S, Pons G, Bech Serra JJ, de la Torre C, de Luna N, Gallardo E, Díaz-Manera J
RhoA/ROCK2 signalling is enhanced by PDGF-AA in fibro-adipogenic progenitor cells: implications for Duchenne muscular dystrophy.
Journal of Cachexia Sarcopenia and Muscle4 Apr 2022, (13)1373–1384. Epub 7 Feb 2022
The lack of dystrophin expression in Duchenne muscular dystrophy (DMD) induces muscle fibre and replacement by fibro-adipose tissue. Although the role of some growth factors in the process of fibrogenesis has been studied, pathways activated by PDGF-AA have not been described so far. Our aim was to study the molecular role of PDGF-AA in the fibrotic process of DMD.
Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.
Blanco B, Ramírez-Fernández Á, Bueno C, Argemí-Muntadas L, Fuentes P, Aguilar-Sopeña Ó, Gutierrez-Agüera F, Zanetti SR, Tapia-Galisteo A, Díez-Alonso L, Segura-Tudela A, Castellà M, Marzal B, Betriu S, Harwood SL, Compte M, Lykkemark S, Erce-Llamazares A, Rubio-Pérez L, Jiménez-Reinoso A, Domínguez-Alonso C, Neves M, Morales P, Paz-Artal E, Guedan S, Sanz L, Toribio ML, Roda-Navarro P, Juan M, Menéndez P, Álvarez-Vallina L
Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers.
Cancer Immunol Res1 Apr 2022, 10(4)498-511.
Chimeric antigen receptor (CAR)-modified T cells have revolutionized the treatment of CD19-positive hematologic malignancies. Although anti-CD19 CAR-engineered autologous T cells can induce remission in patients with B-cell acute lymphoblastic leukemia, a large subset relapse, most of them with CD19-positive disease. Therefore, new therapeutic strategies are clearly needed. Here, we report a comprehensive study comparing engineered T cells either expressing a second-generation anti-CD19 CAR (CAR-T19) or secreting a CD19/CD3-targeting bispecific T-cell engager antibody (STAb-T19). We found that STAb-T19 cells are more effective than CAR-T19 cells at inducing cytotoxicity, avoiding leukemia escape in vitro, and preventing relapse in vivo. We observed that leukemia escape in vitro is associated with rapid and drastic CAR-induced internalization of CD19 that is coupled with lysosome-mediated degradation, leading to the emergence of transiently CD19-negative leukemic cells that evade the immune response of engineered CAR-T19 cells. In contrast, engineered STAb-T19 cells induce the formation of canonical immunologic synapses and prevent the CD19 downmodulation observed in anti-CD19 CAR-mediated interactions. Although both strategies show similar efficacy in short-term mouse models, there is a significant difference in a long-term patient-derived xenograft mouse model, where STAb-T19 cells efficiently eradicated leukemia cells, but leukemia relapsed after CAR-T19 therapy. Our findings suggest that the absence of CD19 downmodulation in the STAb-T19 strategy, coupled with the continued antibody secretion, allows an efficient recruitment of the endogenous T-cell pool, resulting in fast and effective elimination of cancer cells that may prevent CD19-positive relapses frequently associated with CAR-T19 therapies.