The massive exome sequencing reveals new molecular targets in blastic plasmacytoid dendritic cell neoplasm (BPDCN)

La neoplasia Blastica di derivazione dagli elementi Dendritici Plasmacitoidi è una rara ed aggressiva neoplasia ematologica con una prognosi sfavorevole. Non esiste un regime terapeutico standard di prima linea per questi pazienti e solo pochi studi hanno finora esplorato la genetica del BPDCN mostrando un cariotipo complesso e alterazioni genetiche sporadiche. Lo scopo del nostro studio è stato quello di indagare, mediante sequenziamento massivo, lo stato mutazionale di tutto il genoma codificante di 15 casi di BPDCN e della linea cellulare CAL-1. Sulla base di questi dati, abbiamo seguito un approccio di target sequencing per validare, mediante la piattaforma Miseq, mutazioni in 36 geni selezionati. Il WES ha rivelato 199 SNV ricorrenti in 89 geni, tutti legati a condizioni patologiche. I geni più ricorrentemente mutati tra i campioni sono stati ASXL1 e TET2, due regolatori epigenetici, che giocano un ruolo cruciale nella metilazione del DNA e degli istoni e il loro danno porta ad alterazione della struttura della cromatina. Abbiamo quindi deciso di usare i nostri dati di sequenziamento per esplorare il rimodellamento della cromatina nel BPDCN, guardando lo stato mutazionale di tutti i geni coinvolti nella regolazione epigenetica del DNA. Abbiamo trovato 26 geni modificatori epigenetici mutati in quasi tutti i campioni, sei di questi colpiti da mutazioni stop-gain che hanno portato, presumibilmente, ad una perdita funzionale di attività. Partendo proprio da questo punto abbiamo deciso di procedere con la sperimentazione in vivo creando dei modelli murini somministrando 5-Azacitdina, Decitabina e Romidepsina da soli e in combinazione. Inoltre basandoci su studi pregressi abbiamo anche deciso di trattare i topi con Bortezomib. Queste sperimentazioni hanno portato a risultati incoraggianti, specialmente per il trattamento combinato dei topi con Decitabina e Azacitidina che ha portato a riduzione della massa tumorale e maggiore sopravvivenza dei topi trattati rispetto ad i controlli non trattati.Blastic plasmacytoid dendritic cell neoplasm is a rare but aggressive hematologic malignancy with a poor prognosis. There is no first-line standard treatment regimen established for patients with BPDCN and only a few studies explored the genetics of BPDCN showing a complex karyotype and sporadic genetic defects. The aim of our study was to investigate, using deep sequencing, the mutational status of all BPDCN coding genome in 15 BPDCN cases and the CAL-1 cell line. Based on these data, we designed a resequencing approach to identify mutations in 36 selected genes with Miseq platform. WES revealed 199 recurrent SNV (at least 2/16 cases) in 89 genes, all related to pathological conditions. The most recurrent mutated genes, among samples, were ASXL1 and TET2, two epigenetic regulators, that play a crucial role in DNA and histones methylation and their damage alter the chromatin structure. We thus decided to use our exome sequencing data to explore the chromatin remodelling of BPDCN, interrogating the mutational status of all the genes involved into the epigenetic regulation of DNA. We found 26 epigenetic modifier genes mutated in almost all samples and six of them are affected by stop gain mutations presumably leading to a functional loss of chromatin remodelling activity. Starting from this point, we decided to proceed with in vivo testing by creating mouse models by administering 5-Azacitdina, Decitabine and Romidepsine alone and in combination. In addition, we are relying on previous studies we have also decided to treat the mice with Bortezomib. These experiments have led to encouraging results, especially for the combined treatment of mice with Decitabine and Azacitidine, which led to tumor shrinkage and increased survival of treated mice compared to the untreated controls

Correction: Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Dissecting diffuse large B-cell lymphomas of the “not otherwise specified” type: the impact of molecular techniques [version 1; referees: 2 approved]

The updated edition of the Classification of Tumours of Haematopoietic and Lymphoid Tissues, published in September 2017 by the World Health Organization (WHO), presents many important changes to the document published in 2008. Most of these novelties are linked to the exceptional development of biomolecular techniques during the last 10 years. To illustrate how much new technologies have contributed to the better classification of single entities, as well as the discovery of new ones, would go beyond the objectives of this work. For this reason, we will take diffuse large B-cell lymphoma as an example of the cognitive improvement produced by high-yield technologies (such as the gene expression profile, the study of copy number variation, and the definition of the mutational spectrum). The acquisition of this knowledge not only has a speculative value but also represents the elements for effective application in daily practice. On the one hand, it would allow the development of personalised therapy programs, and on the other it would promote the transition from the bench of the researcher's laboratory to the patient's bedside

The identification of TCF1+ progenitor exhausted T cells in THRLBCL may predict a better response to PD-1/PD-L1 blockade

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of diffuse large B-cell lymphoma (DLBCL) that usually affects young to middle-aged patients, with disseminated disease at presentation. The tumor microenvironment (TME) plays a key role in THRLBCL due to its peculiar cellular composition (< 10% neoplastic B cells interspersed in a cytotoxic T-cell/histiocyte-rich background). A significant percentage of THRLBCL is refractory to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-based regimens and to chimeric antigen receptor T-cell therapy; thus, the development of a specific therapeutic approach for these patients represents an unmet clinical need. To better understand the interaction of immune cells in THRLBCL TME and identify more promising therapeutic strategies, we compared the immune gene expression profiles of 12 THRLBCL and 10 DLBCL samples, and further corroborated our findings in an extended in silico set. Gene coexpression network analysis identified the predominant role of the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis in the modulation of the immune response. Furthermore, the PD-1/PD-L1 activation was flanked by the overexpression of 48 genes related to the functional exhaustion of T cells. Globally, THRLBCL TME was highly interferon-inflamed and severely exhausted. The immune gene profiling findings strongly suggest that THRLBCL may be responsive to anti-PD-1 therapy but also allowed us to take a step forward in understanding THRLBCL TME. Of therapeutic relevance, we validated our results by immunohistochemistry, identifying a subset of TCF1(+) (T cell-specific transcription factor 1, encoded by the TCF7 gene) progenitor exhausted T cells enriched in patients with THRLBCL. This subset of TCF1(+) exhausted T cells correlates with good clinical response to immune checkpoint therapy and may improve prediction of anti-PD-1 response in patients with THRLBCL

A multidisciplinary perspective on COVID-19 exit strategies

Lockdowns and associated measures imposed in response to the COVID-19 crisis inflict severe damage to society. Across the globe, scientists and policymakers study ways to lift measures while maintaining control of virus spread in circumstances that continuously change due to the evolution of new variants and increasing vaccination coverage. In this process, it has become clear that finding and analysing exit strategies, which are a key aspect of pandemic mitigation in all consecutive waves of infection, is not solely a matter of epidemiological modeling but has many different dimensions that need to be balanced and therefore requires input from many different disciplines. Here, we document an attempt to investigate exit strategies from a multidisciplinary perspective through the Science versus Corona project in the Netherlands. In this project, scientists and laypeople were challenged to submit (components of) exit strategies. A selection of these were implemented in a formal model, and we have evaluated the scenarios from a multidisciplinary perspective, utilizing expertise in epidemiology, economics, psychology, law, mathematics, and history. We argue for the integration of multidisciplinary perspectives on COVID-19 and more generally in pandemic mitigation, highlight open challenges, and present an agenda for further research into exit strategies and their assessmen

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe