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Cells Oct 2020The actin cytoskeleton plays a crucial role in many cellular processes while its reorganization is important in maintaining cell homeostasis. However, in the case of... (Review)
Review
The actin cytoskeleton plays a crucial role in many cellular processes while its reorganization is important in maintaining cell homeostasis. However, in the case of cancer cells, actin and ABPs (actin-binding proteins) are involved in all stages of carcinogenesis. Literature has reported that ABPs such as SATB1 (special AT-rich binding protein 1), WASP (Wiskott-Aldrich syndrome protein), nesprin, and villin take part in the initial step of carcinogenesis by regulating oncogene expression. Additionally, changes in actin localization promote cell proliferation by inhibiting apoptosis (SATB1). In turn, migration and invasion of cancer cells are based on the formation of actin-rich protrusions (Arp2/3 complex, filamin A, fascin, α-actinin, and cofilin). Importantly, more and more scientists suggest that microfilaments together with the associated proteins mediate tumor vascularization. Hence, the presented article aims to summarize literature reports in the context of the potential role of actin and ABPs in all steps of carcinogenesis.
Topics: Actins; Carcinogenesis; Cell Movement; Humans; Microfilament Proteins
PubMed: 33036298
DOI: 10.3390/cells9102245 -
Haematologica Jun 2024Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the...
Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.
PubMed: 38899342
DOI: 10.3324/haematol.2022.282672 -
Science (New York, N.Y.) Jul 2020Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a...
Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in , which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.
Topics: ADP-Ribosylation Factor 1; Actins; CD4-Positive T-Lymphocytes; Cell Proliferation; Cytokines; Humans; Immunologic Deficiency Syndromes; Lymphoproliferative Disorders; Mechanistic Target of Rapamycin Complex 2; Membrane Proteins; Pedigree; Phosphorylation; Wiskott-Aldrich Syndrome Protein Family
PubMed: 32647003
DOI: 10.1126/science.aay5663 -
Frontiers in Pediatrics 2019The field of primary immunodeficiencies has pioneered many of the advances in haematopoietic stem cell transplantation and cellular therapies over the last 50 years. The... (Review)
Review
The field of primary immunodeficiencies has pioneered many of the advances in haematopoietic stem cell transplantation and cellular therapies over the last 50 years. The first patients to demonstrate sustained benefit and prolonged cure from the primary genetic defect following allogeneic haematopoietic stem cell transplantation were patients with primary immunodeficiencies. Although primary immunodeficiency patients began the modern era of haematopoietic stem cell transplantation, the history is nevertheless short-in answer to the question "what is the long term outcome of patients transplanted for primary immunodeficiencies?" we often have to say that we do not know. We believe that most patients who undergo haematopoietic stem cell transplantation for primary immunodeficiencies should live a normal lifespan with a fully corrected immune system. We are now beginning to understanding long term outcomes, the relationship to the underlying genetic defect, age, and pre-morbid condition of the patient at time of transplantation, stem cell source and donor, and effect of pre-transplant cytoreductive chemotherapy conditioning. The long term consequences of post-transplant complications such as graft vs. host disease, veno-occlusive disease, or immune dysregulation are also being recognized. Additionally, some genetic defects have a systemic distribution, and we are learning the natural history of these defects once the immunodeficiency has been removed.
PubMed: 31737589
DOI: 10.3389/fped.2019.00445 -
Scandinavian Journal of Immunology Jan 2020Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of...
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of these patients develop inflammatory bowel disease (IBD). The mechanisms by which WASp deficiency causes IBD are unclear. Intestinal microbial dysbiosis and imbalances in host immune responses play important roles in the pathogenesis of polygenetic IBD; however, few studies have conducted detailed examination of the microbial alterations and their relationship with IBD in WAS. Here, we collected faecal samples from 19 children (all less than 2 years old) with WAS and samples from WASp-KO mice with IBD and subjected them to 16S ribosomal RNA sequencing. We found that microbial community richness and structure in WAS children were different from those in controls; WAS children revealed reduced microbial community richness and diversity. Relative abundance of Bacteroidetes and Verrucomicrobiain in WAS children was significantly lower, while that of Proteobacteria was markedly higher. WASp-KO mice revealed a significantly decreased abundance of Firmicutes. Faecal microbial dysbiosis caused by WASp deficiency is similar to that observed for polygenetic IBD, suggesting that WASp may play crucial function in microbial homoeostasis and that microbial dysbiosis may contribute to IBD in WAS. These microbial alterations may be useful targets for monitoring and therapeutically managing intestinal inflammation in WAS.
Topics: Animals; Biodiversity; Biomarkers; Case-Control Studies; Child, Preschool; Disease Models, Animal; Dysbiosis; Feces; Female; Gastrointestinal Microbiome; Humans; Infant; Inflammatory Bowel Diseases; Male; Metagenome; Metagenomics; Mice; Mice, Knockout; Mutation; RNA, Ribosomal, 16S; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 31267543
DOI: 10.1111/sji.12805 -
International Journal of Molecular... Apr 2021In the last decade, improvements in genetic testing have revolutionized the molecular diagnosis of inherited thrombocytopenias (ITs), increasing the spectrum of... (Review)
Review
In the last decade, improvements in genetic testing have revolutionized the molecular diagnosis of inherited thrombocytopenias (ITs), increasing the spectrum of knowledge of these rare, complex and heterogeneous disorders. In contrast, the therapeutic management of ITs has not evolved in the same way. Platelet transfusions have been the gold standard treatment for a long time. Thrombopoietin receptor agonists (TPO-RA) were approved for immune thrombocytopenia (ITP) ten years ago and there is evidence for the use of TPO-RA not only in other forms of ITP, but also in ITs. We have reviewed in the literature the existing evidence on the role of TPO-RAs in ITs from 2010 to February 2021. A total of 24 articles have been included, 4 clinical trials, 3 case series and 17 case reports. A total of 126 patients with ITs have received TPO-RA. The main diagnoses were Wiskott-Aldrich syndrome, MYH9-related disorder and ANKRD26-related thrombocytopenia. Most patients were enrolled in clinical trials and were treated for short periods of time with TPO-RA as bridging therapies towards surgical interventions, or other specific approaches, such as hematopoietic stem cell transplantation. Here, we have carried out an updated and comprehensive review about the efficacy and safety of TPO-RA in ITs.
Topics: Disease Management; Genetic Diseases, Inborn; Hearing Loss, Sensorineural; Humans; Intercellular Signaling Peptides and Proteins; Myosin Heavy Chains; Platelet Transfusion; Receptors, Thrombopoietin; Thrombocytopenia; Treatment Outcome; Wiskott-Aldrich Syndrome
PubMed: 33919295
DOI: 10.3390/ijms22094330 -
Frontiers in Immunology 2022Primary immunodeficiency diseases (PIDs) are a group of rare inherited disorders affecting the immune system that can be conventionally treated with allogeneic... (Review)
Review
Primary immunodeficiency diseases (PIDs) are a group of rare inherited disorders affecting the immune system that can be conventionally treated with allogeneic hematopoietic stem cell transplantation and with experimental autologous gene therapy. With both approaches still facing important challenges, gene editing has recently emerged as a potential valuable alternative for the treatment of genetic disorders and within a relatively short period from its initial development, has already entered some landmark clinical trials aimed at tackling several life-threatening diseases. In this review, we discuss the progress made towards the development of gene editing-based therapeutic strategies for PIDs with a special focus on Wiskott - Aldrich syndrome and outline their main challenges as well as future directions with respect to already established treatments.
Topics: Gene Editing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 36059471
DOI: 10.3389/fimmu.2022.966084 -
ELife Nov 2020The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune...
The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitution in vitro and in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.
Topics: Autophagy; Cell Line; Gene Expression Regulation; Homeostasis; Humans; Macrophages; Mitochondria; Wiskott-Aldrich Syndrome Protein
PubMed: 33135633
DOI: 10.7554/eLife.55547 -
Jornal de Pediatria 2021The aim of the report is to describe the main immunodeficiencies with syndromic characteristics according to the new classification of Inborn Errors of Immunity. (Review)
Review
OBJECTIVES
The aim of the report is to describe the main immunodeficiencies with syndromic characteristics according to the new classification of Inborn Errors of Immunity.
DATA SOURCE
The data search was centered on the PubMed platform on review studies, meta-analyses, systematic reviews, case reports and a randomized study published in the last 10 years that allowed the characterization of the several immunological defects included in this group.
DATA SYNTHESIS
Immunodeficiencies with syndromic characteristics include 65 immunological defects in 9 subgroups. The diversity of clinical manifestations is observed in each described disease and may appear early or later, with variable severity. Congenital thrombocytopenia, syndromes with DNA repair defect, immuno-osseous dysplasias, thymic defects, Hyper IgE Syndrome, anhidrotic ectodermal dysplasia with immunodeficiency and purine nucleoside phosphorylase deficiency were addressed.
CONCLUSIONS
Immunological defects can present with very different characteristics; however, the occurrence of infectious processes, autoimmune disorders and progression to malignancy may suggest diagnostic research. In the case of diseases with gene mutations, family history is of utmost importance.
Topics: Humans; Immunologic Deficiency Syndromes; Phenotype; Primary Immunodeficiency Diseases; Purine-Nucleoside Phosphorylase; Purine-Pyrimidine Metabolism, Inborn Errors
PubMed: 33347837
DOI: 10.1016/j.jped.2020.10.015 -
Frontiers in Immunology 2021Modified or misplaced DNA can be recognized as a danger signal by mammalian cells. Activation of cellular responses to DNA has evolved as a defense mechanism to... (Review)
Review
Modified or misplaced DNA can be recognized as a danger signal by mammalian cells. Activation of cellular responses to DNA has evolved as a defense mechanism to microbial infections, cellular stress, and tissue damage, yet failure to control this mechanism can lead to autoimmune diseases. Several monogenic and multifactorial autoimmune diseases have been associated with type-I interferons and interferon-stimulated genes (ISGs) induced by deregulated recognition of self-DNA. Hence, understanding how cellular mechanism controls the pathogenic responses to self-nucleic acid has important clinical implications. Fine-tuned membrane trafficking and cellular compartmentalization are two major factors that balance activation of DNA sensors and availability of self-DNA ligands. Intracellular transport and organelle architecture are in turn regulated by cytoskeletal dynamics, yet the precise impact of actin remodeling on DNA sensing remains elusive. This review proposes a critical analysis of the established and hypothetical connections between self-DNA recognition and actin dynamics. As a paradigm of this concept, we discuss recent evidence of deregulated self-DNA sensing in the prototypical actin-related primary immune deficiency (Wiskott-Aldrich syndrome). We anticipate a broader impact of actin-dependent processes on tolerance to self-DNA in autoimmune disorders.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Cytoskeleton; DNA; Endosomes; Humans; Membrane Proteins; Nucleotidyltransferases; Phagocytes; Protein Binding; Protein Transport; Signal Transduction; Toll-Like Receptor 9
PubMed: 34084165
DOI: 10.3389/fimmu.2021.657344