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International Journal of Molecular... Jan 2021Increasing evidence indicates that cancer metastasis is regulated by specific genetic pathways independent of those controlling tumorigenesis and cancer growth. WASF3, a... (Review)
Review
Increasing evidence indicates that cancer metastasis is regulated by specific genetic pathways independent of those controlling tumorigenesis and cancer growth. WASF3, a Wiskott-Aldrich syndrome protein family member, appears to play a major role not only in the regulation of actin cytoskeleton dynamics but also in cancer cell invasion/metastasis. Recent studies have highlighted that WASF3 is a master regulator and acts as a pivotal scaffolding protein, bringing the various components of metastatic signaling complexes together both spatially and temporally. Herein, targeting WASF3 at the levels of transcription, protein stability, and phosphorylation holds great promise for metastasis suppression, regardless of the diverse genetic backgrounds associated with tumor development. This review focuses on the critical and distinct contributions of WASF3 in the regulation of signal pathways promoting cancer cell invasion and metastasis.
Topics: ATPases Associated with Diverse Cellular Activities; Animals; Cell Movement; Endoplasmic Reticulum Chaperone BiP; Gene Expression Regulation, Neoplastic; HSP70 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Janus Kinase 2; Membrane Proteins; Mice; MicroRNAs; Mitochondrial Proteins; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; STAT3 Transcription Factor; Signal Transduction; Wiskott-Aldrich Syndrome Protein Family
PubMed: 33467681
DOI: 10.3390/ijms22020836 -
Frontiers in Immunology 2023The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp)...
The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for immune synapse formation. Patients with WAS show reduced numbers of peripheral blood T lymphocytes and an altered T-cell receptor repertoire. , their peripheral T cells show decreased proliferation and cytokine production upon aCD3/aCD28 stimulation. It is unclear whether these T-cell defects are acquired during peripheral activation or are, in part, generated during thymic development. Here, we assessed the role of WASp during T-cell differentiation using artificial thymic organoid cultures and in the thymus of humanized mice. Although CRISPR/Cas9 WAS knockout hematopoietic stem and progenitor cells (HSPCs) rearranged the T-cell receptor and differentiated to T-cell receptor (TCR) CD4 CD8 double-positive (DP) cells similar to wild-type HSPCs, a partial defect in the generation of CD8 single-positive (SP) cells was observed, suggesting that WASp is involved in their positive selection. TCR repertoire analysis of the DP and CD8 SP population, however, showed a polyclonal repertoire with no bias toward autoreactivity. To our knowledge, this is the first study of the role of WASp in human T-cell differentiation and on TCR repertoire generation.
Topics: Humans; Animals; Mice; Wiskott-Aldrich Syndrome Protein; Cell Lineage; Wiskott-Aldrich Syndrome; Receptors, Antigen, T-Cell; Cell Differentiation
PubMed: 37350958
DOI: 10.3389/fimmu.2023.1188099 -
Diagnostics (Basel, Switzerland) Sep 2022Eczema is a classical characteristic not only in atopic dermatitis but also in various genodermatosis. Patients suffering from primary immunodeficiency diseases such as... (Review)
Review
Eczema is a classical characteristic not only in atopic dermatitis but also in various genodermatosis. Patients suffering from primary immunodeficiency diseases such as hyper-immunoglobulin E syndromes, Wiskott-Aldrich syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, STAT5B deficiency, Omenn syndrome, atypical complete DiGeorge syndrome; metabolic disorders such as acrodermatitis enteropathy, multiple carboxylase deficiency, prolidase deficiency; and other rare syndromes like severe dermatitis, multiple allergies and metabolic wasting syndrome, Netherton syndrome, and peeling skin syndrome frequently perform with eczema-like lesions. These genodermatosis may be misguided in the context of eczematous phenotype. Misdiagnosis of severe disorders unavoidably affects appropriate treatment and leads to irreversible outcomes for patients, which underlines the importance of molecular diagnosis and genetic analysis. Here we conclude clinical manifestations, molecular mechanism, diagnosis and management of several eczema-related genodermatosis and provide accessible advice to physicians.
PubMed: 36140582
DOI: 10.3390/diagnostics12092177 -
Blood Mar 2022Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT...
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged <5 years at HSCT had a significantly better overall survival. The overall cumulative incidences of grade III to IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6% and 2.1%, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure and mixed donor chimerism and more frequently underwent secondary procedures (second HSCT, unconditioned stem cell boost, donor lymphocyte infusion, or splenectomy). In summary, HSCT for WAS with conditioning regimens currently recommended by IEWP results in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age ≥5 years remains a risk factor for overall survival.
Topics: Busulfan; Child, Preschool; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Tissue Donors; Transplantation Conditioning; Treatment Outcome; Wiskott-Aldrich Syndrome
PubMed: 35100336
DOI: 10.1182/blood.2021014687 -
Pediatric Allergy and Immunology :... Jan 2022Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy-related symptoms as fundamental features. In patients with PADs, primary immune... (Review)
Review
Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy-related symptoms as fundamental features. In patients with PADs, primary immune deficiency and immune dysregulation symptoms are usually coexist. Chronic skin disease, manifesting with erythroderma, severe atopic dermatitis or eczema, and urticaria, is one of the main features observed in PADs, such as hyper-IgE syndromes, Omenn syndrome, Wiskott-Aldrich syndrome, IPEX-linked syndrome, skin barrier disorders, as well as some autoinflammatory diseases. The recognition of PADs in the context of an allergic phenotype is crucial to ensure prompt diagnosis and appropriate treatment. This article provides an overview of the main PADs with skin involvement.
Topics: Eczema; Humans; Hypersensitivity, Immediate; Job Syndrome; Skin Diseases; Urticaria
PubMed: 35080318
DOI: 10.1111/pai.13633 -
Frontiers in Pediatrics 2019Both Wiskott-Aldrich syndrome (WAS) and dedicator of cytokinesis 8 (DOCK8) deficiency are primary immunodeficiency diseases caused by mutations in genes that result in... (Review)
Review
Both Wiskott-Aldrich syndrome (WAS) and dedicator of cytokinesis 8 (DOCK8) deficiency are primary immunodeficiency diseases caused by mutations in genes that result in defective organization of the cytoskeleton in hematopoietic tissues. They share some overlapping features such as a combined immunodeficiency, eczema and a predisposition to autoimmunity and malignancy, but also have some unique features that make them relatively easy to diagnose by clinical means. Both diseases can be cured by HSCT in a large proportion of patients. In WAS it is sometimes difficult to establish an indication for HSCT due to the large variability of disease severity, while HSCT is probably indicated in all patients affected by DOCK8 deficiency. There is considerably more published HSCT experience for WAS than for DOCK8 deficiency, but many open questions remain, which will be discussed in this review.
PubMed: 31750279
DOI: 10.3389/fped.2019.00451 -
Clinical and Experimental Dental... Feb 2022Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency, characterized by micro-thrombocytopenia, recurrent infections, and eczema. This study aims to... (Review)
Review
OBJECTIVE
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency, characterized by micro-thrombocytopenia, recurrent infections, and eczema. This study aims to describe common oral manifestations and evaluate oral microbioma of WAS patients.
MATERIAL AND METHODS
In this cohort study, 11 male WAS patients and 16 male healthy controls were evaluated in our Center between 2010 and 2018. Data about clinical history, oral examination, Gingival Index (GI) and Plaque Index (PI) were collected from both groups. Periodontal microbiological flora was evaluated on samples of the gingival sulcus.
RESULTS
WAS subjects presented with premature loss of deciduous and permanent teeth, inclusions, eruption disturbance, and significantly worse GI and PI. They also showed a trend toward a higher total bacterial load. Fusobacterium nucleatum, reported to contribute to periodontitis onset, was the most prevalent bacteria, together with Porphyromonas gingivalis and Tannerella forsythia.
CONCLUSIONS
Our data suggest that WAS patients are at greater risk of alterations in the oral cavity. The statistically higher incidence of periodontitis and the trend to higher prevalence of potentially pathological bacterial species in our small cohort, that should be confirmed in future in a larger population, underline the importance of dentistry monitoring as part of the multidisciplinary management of WAS patients.
Topics: Aggregatibacter actinomycetemcomitans; Child; Cohort Studies; Female; Humans; Male; Microbiota; Periodontitis; Prevotella intermedia; Wiskott-Aldrich Syndrome
PubMed: 35199474
DOI: 10.1002/cre2.503 -
Frontiers in Immunology 2023Phosphorylation of diacylglycerol by diacylglycerol-kinases represents a major inhibitory event constraining T cell activation upon antigen engagement. Efficient TCR...
BACKGROUND
Phosphorylation of diacylglycerol by diacylglycerol-kinases represents a major inhibitory event constraining T cell activation upon antigen engagement. Efficient TCR signalling requires the inhibition of the alpha isoform of diacylglycerol kinase, DGKα, by an unidentified signalling pathway triggered by the protein adaptor SAP. We previously demonstrated that, in SAP absence, excessive DGKα activity makes the T cells resistant to restimulation-induced cell death (RICD), an apoptotic program counteracting excessive T cell clonal expansion.
RESULTS
Herein, we report that the Wiskott-Aldrich syndrome protein (WASp) inhibits DGKα through a specific interaction of the DGKα recoverin homology domain with the WH1 domain of WASp. Indeed, WASp is necessary and sufficient for DGKα inhibition, and this WASp function is independent of ARP2/3 activity. The adaptor protein NCK-1 and the small G protein CDC42 connect WASp-mediated DGKα inhibition to SAP and the TCR signalosome. In primary human T cells, this new signalling pathway is necessary for a full response in terms of IL-2 production, while minimally affecting TCR signalling and restimulation-induced cell death. Conversely, in T cells made resistant to RICD by SAP silencing, the enhanced DAG signalling due to DGKα inhibition is sufficient to restore apoptosis sensitivity.
CONCLUSION
We discover a novel signalling pathway where, upon strong TCR activation, the complex between WASp and DGKα blocks DGKα activity, allowing a full cytokine response.
Topics: Humans; Diacylglycerol Kinase; Diglycerides; Interleukin-2; Receptors, Antigen, T-Cell; Wiskott-Aldrich Syndrome Protein
PubMed: 37138877
DOI: 10.3389/fimmu.2023.1043603 -
Clinical and Translational Medicine Apr 2022
Topics: Genetic Therapy; Humans; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35437889
DOI: 10.1002/ctm2.815 -
Biomedicines Sep 2021The Wiskott-Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE)-WAVE1, WAVE2 and WAVE3 regulate rapid reorganization of cortical actin... (Review)
Review
The Wiskott-Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE)-WAVE1, WAVE2 and WAVE3 regulate rapid reorganization of cortical actin filaments and have been shown to form a key link between small GTPases and the actin cytoskeleton. Upon receiving upstream signals from Rho-family GTPases, the WASP and WAVE family proteins play a significant role in polymerization of actin cytoskeleton through activation of actin-related protein 2/3 complex (Arp2/3). The Arp2/3 complex, once activated, forms actin-based membrane protrusions essential for cell migration and cancer cell invasion. Thus, by activation of Arp2/3 complex, the WAVE and WASP family proteins, as part of the WAVE regulatory complex (WRC), have been shown to play a critical role in cancer cell invasion and metastasis, drawing significant research interest over recent years. Several studies have highlighted the potential for targeting the genes encoding either part of or a complete protein from the WASP/WAVE family as therapeutic strategies for preventing the invasion and metastasis of cancer cells. WAVE2 is well documented to be associated with the pathogenesis of several human cancers, including lung, liver, pancreatic, prostate, colorectal and breast cancer, as well as other hematologic malignancies. This review focuses mainly on the role of WAVE2 in the development, invasion and metastasis of different types of cancer. This review also summarizes the molecular mechanisms that regulate the activity of WAVE2, as well as those oncogenic pathways that are regulated by WAVE2 to promote the cancer phenotype. Finally, we discuss potential therapeutic strategies that target WAVE2 or the WAVE regulatory complex, aimed at preventing or inhibiting cancer invasion and metastasis.
PubMed: 34572403
DOI: 10.3390/biomedicines9091217