RESUMO
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a rare disease first reported in 2020, most commonly seen in men aged 56-75 years old. Common clinical features include skin lesions (83.5%), fever (63.6%), relapsing chondritis (36.4%), venous thrombosis (34.7%) and lymph node enlargement (33.9%). The patient is a man in his 40s who presented with testicular and lower extremity pain, followed by a rash and bicytopenia. He was initiated on corticosteroids and sulfasalazine. He was found to have mediastinal lymphadenopathy and underwent an endobronchial ultrasound and transbronchial needle aspiration followed by a video-assisted thoracic surgery biopsy which were unrevealing. Eventually, an ubiquitin-like modifier activating enzyme (UBA-1) gene analysis was performed that was consistent with VEXAS syndrome. Patients with VEXAS syndrome usually present with a red or violaceous rash and dyspnoea. Laboratory abnormalities include anaemia, elevated mean corpuscular volume, thrombocytopenia and elevated inflammatory markers. Diagnosis is based on the genetic mutation and associated symptoms. The treatment includes steroids and Janus kinase (JAK) inhibitors, specifically ruxolitinib.
Assuntos
Linfadenopatia , Humanos , Masculino , Linfadenopatia/etiologia , Adulto , Enzimas Ativadoras de Ubiquitina/genética , Doenças do Mediastino/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Diagnóstico Diferencial , Síndrome , Nitrilas , Pirazóis , PirimidinasRESUMO
INTRODUCTION: VEXAS syndrome, characterized by a UBA1 gene mutation, is a rare and severe systemic inflammatory disease predominantly affecting men. Since its initial description in 2020, it has been noted for its broad clinical phenotype and frequent misdiagnosis. CASE PRESENTATION: A 76-year-old Caucasian male patient diagnosed with VEXAS syndrome is presented in this case report. He presented with typical symptoms including pulmonary manifestations (infiltrates and effusions), systemic inflammation, and haematological abnormalities. The diagnosis was challenging due to the disease's heterogeneous presentation, often resembling autoimmune or haematological diseases. This patient's case featured ground-glass opacities and pleural effusions, underlining the significant pulmonary involvement seen in 50-67% of VEXAS patients. His condition was further complicated by recurrent fever and systemic inflammation affecting multiple organs. CONCLUSION: VEXAS syndrome demands an aggressive treatment approach due to its high mortality rate and refractory nature. This case underscores the importance of including VEXAS syndrome in differential diagnoses, particularly for patients with systemic inflammation and pulmonary symptoms, and calls for multidisciplinary management and extensive research to understand its full range of clinical phenotypes.
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Fenótipo , Derrame Pleural , Enzimas Ativadoras de Ubiquitina , Humanos , Idoso , Masculino , Derrame Pleural/diagnóstico , Enzimas Ativadoras de Ubiquitina/genética , Diagnóstico Diferencial , Mutação , InflamaçãoRESUMO
Ubiquitin like modifier activating enzyme 1 (UBA1) plays an important role in immune regulation and cellular function. However, the functional mechanism and role of UBA1 in pan-cancer have not been fully elucidated and its value in haematological tumours (diffuse large B cell lymphoma (DLBC/DLBCL) and acute myeloid leukaemia (AML/LAML)) has not been explored. We conducted a comprehensive analysis of the functional mechanism and role of UBA1 in pan-cancer using multiple databases, including differential expression analysis, clinical pathological staging analysis, prognosis analysis and immune analysis. Then, we confirmed the function of UBA1 in haematological tumours through cell experiments. The results showed that the expression of UBA1 was significantly increased in most cancers and the differential expression of UBA1 was mainly concentrated in digestive tumours, haematological tumours and brain tumours. Moreover, the high expression of UBA1 had poor prognosis in most tumours, which may be related to its involvement in various cancer-related pathways such as cell cycle, as well as its methylation level, protein phosphorylation level, immune cell infiltration and immune therapy response. Cell experiments have confirmed that UBA1 can significantly regulate the cycle progression and apoptosis of DLBCL cells and AML cells. Therefore, UBA1 may be a potential therapeutic target for haematological tumours. In summary, our study not only comprehensively analysed the functional mechanisms and clinical value of UBA1 in pan-cancer, but also validated for the first time the regulatory role of UBA1 in haematological tumours.
Assuntos
Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Enzimas Ativadoras de Ubiquitina , Humanos , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/genética , Prognóstico , Biologia Computacional/métodos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/genética , Linhagem Celular Tumoral , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Apoptose , Proliferação de CélulasRESUMO
UFMylation is a highly conserved ubiquitin-like post-translational modification that catalyzes the covalent linkage of UFM1 to its target proteins. This modification plays a critical role in the maintenance of endoplasmic reticulum proteostasis, DNA damage response, autophagy, and transcriptional regulation. Mutations in UFM1, as well as in its specific E1 enzyme UBA5 and E2 enzyme UFC1, have been genetically linked to microcephaly. Our previous research unveiled the important role of UFMylation in regulating mitosis. However, the underlying mechanisms have remained unclear due to the limited identification of substrates. In this study, we identified Eg5, a motor protein crucial for mitotic spindle assembly and maintenance, as a novel substrate for UFMylation and identified Lys564 as the crucial UFMylation site. UFMylation did not alter its transcriptional level, phosphorylation level, or protein stability, but affected the mono-ubiquitination of Eg5. During mitosis, Eg5 and UFM1 co-localize at the centrosome and spindle apparatus, and defective UFMylation leads to diminished spindle localization of Eg5. Notably, the UFMylation-defective Eg5 mutant (K564R) exhibited shorter spindles, metaphase arrest, spindle checkpoint activation, and a failure of cell division in HeLa cells. Overall, Eg5 UFMylation is essential for proper spindle organization, mitotic progression, and cell proliferation.
Assuntos
Cinesinas , Mitose , Fuso Acromático , Ubiquitinação , Humanos , Fuso Acromático/metabolismo , Células HeLa , Cinesinas/metabolismo , Cinesinas/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/genética , Células HEK293 , Centrossomo/metabolismo , Processamento de Proteína Pós-Traducional , ProteínasRESUMO
Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.
Assuntos
Acetaminofen , Cardiolipinas , Doença Hepática Induzida por Substâncias e Drogas , Ciclopentanos , Proteína NEDD8 , Pirimidinas , Acetaminofen/efeitos adversos , Animais , Proteína NEDD8/metabolismo , Proteína NEDD8/genética , Humanos , Pirimidinas/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Cardiolipinas/metabolismo , Camundongos , Ciclopentanos/farmacologia , Masculino , Fígado/metabolismo , Fígado/patologia , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Transdução de Sinais/efeitos dos fármacos , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidoresRESUMO
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently characterized disease associated with somatic mutations in the UBA1 gene, which cause dysregulation of ubiquitin-mediated processes. This case describes a 71-year-old male patient with VEXAS syndrome who presented with refractory lung inflammation with a pattern similar to computed tomography hypersensitivity pneumonitis, a novel finding in VEXAS syndrome. The presented clinical case highlights the protean involvement of the lung in VEXAS syndrome and emphasizes the importance of considering interstitial lung disease in the differential diagnosis.
Assuntos
Alveolite Alérgica Extrínseca , Enzimas Ativadoras de Ubiquitina , Humanos , Masculino , Idoso , Alveolite Alérgica Extrínseca/genética , Alveolite Alérgica Extrínseca/diagnóstico , Enzimas Ativadoras de Ubiquitina/genética , Síndrome , Vacúolos , Diagnóstico Diferencial , Tomografia Computadorizada por Raios X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/complicações , Mutação , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pulmão/patologiaRESUMO
VEXAS syndrome is a rare entity secondary to UBA1 gene mutations, located on the X chromosome. This mutation generates, as a consequence, a characteristic vacuolation on haematopoietic stem-cells. It is characterized by multiple autoinflammatory and haematologic manifestations, which respond and end up being dependent on corticosteroid treatment. In this publication we present a 2-case series diagnosed at our hospital and make a brief literature review of the published evidence so far.
Assuntos
Enzimas Ativadoras de Ubiquitina , Humanos , Mutação , Enzimas Ativadoras de Ubiquitina/genéticaRESUMO
VEXAS syndrome is a recently described autoinflammatory syndrome caused by the somatic acquisition of UBA1 mutations in myeloid precursors and is frequently associated with hematologic malignancies, chiefly myelodysplastic syndromes. Disease presentation can mimic several rheumatologic disorders, delaying the diagnosis. We describe a case of atypical presentation resembling late-onset axial spondylarthritis, later progressing to a systemic inflammatory syndrome with chondritis, cutaneous vasculitis, and transfusion-dependent anemia, requiring high doses of steroids. Ruxolitinib was used as the first steroid-sparing strategy without response. However, azacitidine showed activity in controlling both inflammation and the mutant clone. This case raises the question of whether azacitidine's anti-inflammatory effects are dependent on or independent of clonal control. We discuss the potential relevance of molecular remission in VEXAS syndrome and highlight the importance of a multidisciplinary team for the care of such complex patients.
Assuntos
Azacitidina , Sacroileíte , Enzimas Ativadoras de Ubiquitina , Humanos , Azacitidina/uso terapêutico , Sacroileíte/tratamento farmacológico , Sacroileíte/diagnóstico , Sacroileíte/genética , Enzimas Ativadoras de Ubiquitina/genética , Mutação , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/diagnósticoRESUMO
UBA5, a ubiquitin-like activated enzyme involved in ufmylation and sumoylation, presents a viable target for pancreatic and breast cancer treatments, yet its role in lung adenocarcinoma (LUAD) remains underexplored. This study reveals UBA5's tumor-promoting effect in LUAD, as evidenced by its upregulation in patients and positive correlation with TNM stages. Elevated UBA5 levels predict poor outcomes for these patients. Pharmacological inhibition of UBA5 using DKM 2-93 significantly curtails the growth of A549, H1299, and cisplatin-resistant A549 (A549/DDP) LUAD cells in vitro. Additionally, UBA5 knockdown via shRNA lentivirus suppresses tumor growth both in vitro and in vivo. High UBA5 expression adversely alters the tumor immune microenvironment, affecting immunostimulators, MHC molecules, chemokines, receptors, and immune cell infiltration. Notably, UBA5 expression correlates positively with M2 macrophage infiltration, the predominant immune cells in LUAD. Co-culture experiments further demonstrate that UBA5 knockdown directly inhibits M2 macrophage polarization and lactate production in LUAD. Moreover, in vivo studies show reduced M2 macrophage infiltration following UBA5 knockdown. UBA5 expression is also associated with increased tumor heterogeneity, including tumor mutational burden, microsatellite instability, neoantigen presence, and homologous recombination deficiency. Experiments indicate that UBA5 overexpression promotes cisplatin resistance in vitro, whereas UBA5 inhibition enhances cisplatin sensitivity in both in vitro and in vivo settings. Overall, these findings suggest that targeting UBA5 inhibits LUAD by impeding cancer cell proliferation, M2 macrophage polarization, and cisplatin resistance.
Assuntos
Adenocarcinoma de Pulmão , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Humanos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Animais , Camundongos , Proliferação de Células/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Feminino , Microambiente Tumoral/efeitos dos fármacos , Camundongos Nus , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Masculino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Doxorubicin (DOX) is a widely utilized chemotherapeutic agent in clinical oncology for treating various cancers. However, its clinical use is constrained by its significant side effects. Among these, the development of cardiomyopathy, characterized by cardiac remodeling and eventual heart failure, stands as a major concern following DOX chemotherapy. In our current investigation, we have showcased the efficacy of MLN4924 in mitigating doxorubicin-induced cardiotoxicity through direct inhibition of the NEDD8-activating enzyme, NAE. MLN4924 demonstrated the ability to stabilize mitochondrial function post-doxorubicin treatment, diminish cardiomyocyte apoptosis, alleviate oxidative stress-induced damage in the myocardium, enhance cardiac contractile function, mitigate cardiac fibrosis, and impede cardiac remodeling associated with heart failure. At the mechanistic level, MLN4924 intervened in the neddylation process by inhibiting the NEDD8 activating enzyme, NAE, within the murine cardiac tissue subsequent to doxorubicin treatment. This intervention resulted in the suppression of NEDD8 protein expression, reduction in neddylation activity, and consequential manifestation of cardioprotective effects. Collectively, our findings posit MLN4924 as a potential therapeutic avenue for mitigating doxorubicin-induced cardiotoxicity by attenuating heightened neddylation activity through NAE inhibition, thereby offering a viable and promising treatment modality for afflicted patients.
Assuntos
Cardiotoxicidade , Ciclopentanos , Doxorrubicina , Miócitos Cardíacos , Proteína NEDD8 , Pirimidinas , Animais , Camundongos , Apoptose/efeitos dos fármacos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/patologia , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Ciclopentanos/farmacologia , Ciclopentanos/uso terapêutico , Doxorrubicina/efeitos adversos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteína NEDD8/metabolismo , Proteína NEDD8/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Pirimidinas/farmacologia , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/genéticaRESUMO
INTRODUCTION: Idiopathic Multicentric Castleman Disease (iMCD) is a complex and poorly understood pathophysiological entity, which encompasses a variety of conditions and can mimic or be associated with autoimmune/autoinflammatory diseases, making it challenging to diagnose and treat. Vacuoles, Enzyme E1, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an adult-onset autoinflammatory disorder associated with hematological abnormalities and caused by acquired somatic mutations in the ubiquitin-like modifier activating enzyme 1 gene (UBA1) which shares several common clinical and biological signs with iMCD. In this article, we report a patient with VEXAS syndrome initially presenting as iMCD, questioning the link between these two entities. CASE DESCRIPTION: We report here a patient initially presenting as iMCD, proved on lymph node histology, which turns out to have a mutation at the splice acceptor site of exon 3 of UBA1 exhibiting VEXAS syndrome with Castleman-like lymph node. CONCLUSION: This is only the second case of VEXAS syndrome presenting as iMCD. VEXAS syndrome should therefore be considered in the presence of iMCD suspicion, including in cases of compatible histology.
Assuntos
Hiperplasia do Linfonodo Gigante , Enzimas Ativadoras de Ubiquitina , Humanos , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/genética , Diagnóstico Diferencial , Enzimas Ativadoras de Ubiquitina/genética , Masculino , Síndrome , Mutação , Linfonodos/patologia , Adulto , Pessoa de Meia-IdadeRESUMO
VEXAS syndrome is a new disease entity characterized by the presence of cytoplasmic vacuoles in blood cells, X-linked autoinflammatory symptoms, and somatic variants in UBA1, which encodes an E1 ubiquitin-activating enzyme. Around 30-50% of VEXAS syndrome patients have concurrent MDS. We and others have recently analyzed clinical and genetic features of MDS associated with VEXAS syndrome and found that most of these cases are categorized in the low-risk subgroup with low bone marrow blast percentages. MDS associated with VEXAS syndrome tended to involve a smaller number of genes and lower-risk genetic alterations than classical MDS. In addition, anemia in MDS associated with VEXAS syndrome with active inflammation before treatment tended to respond well to steroids. In this review, we will present our recent findings together with others, focusing on the new disease entity and pathophysiology of VEXAS syndrome and clinical/genetic features of associated MDS.
Assuntos
Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Enzimas Ativadoras de Ubiquitina/genéticaRESUMO
BACKGROUND: VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a hematoinflammatory disease that typically affects adults. It results from a somatic mutation of the E1 ubiquitin conjugating enzyme encoded by the UBA1 gene. VEXAS is frequently accompanied by myelodysplastic syndrome (MDS). The purpose of this study is to describe the ocular and orbital manifestations of VEXAS patients in a case series in our medical centre. METHODS: A retrospective chart review was performed for all patients who were diagnosed with VEXAS syndrome in a tertiary medical centre over two years. RESULTS: Eight patients were identified with VEXAS. In six patients, the diagnosis was confirmed by genomic sequencing. Two patients were identified based on their phenotype. All patients were males. The mean age at diagnosis was 78.7 years. In two patients, the ocular manifestation was the presenting symptom for VEXAS. Seven patients (87.5%) had history of MDS. Systemic inflammation manifestations include: skin rash (n = 5), recurrent fevers (n = 2), relapsing polychondritis (n = 2), pleuritis and pleural effusion (n = 2), poly arteritis nodosa- PAN (n = 1) and thrombophlebitis (n = 1). Seven (87%) patients were presented with periorbital oedema. Three patients showed orbital inflammation. Dacryoadenitis was observed in two patients, and extraocular muscle (EOM) myositis was detected in two patients. Four patients demonstrated ocular inflammation such as: episcleritis, scleritis and anterior uveitis. CONCLUSION: ocular manifestations in VEXAS include orbital inflammation, dacryoadenitis, myositis, uveitis, scleritis, episcleritis and periorbital oedema. We recommend that in old male patients, with history of haematological disorder, presenting with ocular symptom, VEXAS investigation should be taken into consideration.
Assuntos
Doenças Orbitárias , Humanos , Masculino , Estudos Retrospectivos , Idoso , Idoso de 80 Anos ou mais , Doenças Orbitárias/etiologia , Doenças Orbitárias/diagnóstico , Pessoa de Meia-Idade , Enzimas Ativadoras de Ubiquitina/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Esclerite/diagnóstico , Esclerite/etiologia , Oftalmopatias/etiologia , Oftalmopatias/genética , Oftalmopatias/diagnóstico , Mutação , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/complicaçõesRESUMO
Adult T-cell leukemia (ATL), caused by HTLV-1, is the most lethal hematological malignancy. NEDD8-activating enzyme (NAE) is a component of the NEDD8 conjunction pathway that regulates cullin-RING ubiquitin ligase (CRL) activity. HTLV-1-infected T cells expressed higher levels of NAE catalytic subunit UBA3 than normal peripheral blood mononuclear cells. NAE1 knockdown inhibited proliferation of HTLV-1-infected T cells. The NAE1 inhibitor MLN4924 suppressed neddylation of cullin and inhibited the CRL-mediated turnover of tumor suppressor proteins. MLN4924 inhibited proliferation of HTLV-1-infected T cells by inducing DNA damage, leading to S phase arrest and caspase-dependent apoptosis. S phase arrest was associated with CDK2 and cyclin A downregulation. MLN4924-induced apoptosis was mediated by the upregulation of pro-apoptotic and downregulation of anti-apoptotic proteins. Furthermore, MLN4924 inhibited NF-κB, AP-1, and Akt signaling pathways and activated JNK. Therefore, neddylation inhibition is an attractive strategy for ATL therapy. Our findings support the use of MLN4924 in ATL clinical trials.
Assuntos
Apoptose , Proliferação de Células , Ciclopentanos , Vírus Linfotrópico T Tipo 1 Humano , Proteína NEDD8 , NF-kappa B , Proteínas Proto-Oncogênicas c-akt , Pirimidinas , Transdução de Sinais , Fator de Transcrição AP-1 , Enzimas Ativadoras de Ubiquitina , Humanos , Pirimidinas/farmacologia , NF-kappa B/metabolismo , Fator de Transcrição AP-1/metabolismo , Ciclopentanos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose/efeitos dos fármacos , Proteína NEDD8/metabolismo , Proliferação de Células/efeitos dos fármacos , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/genética , Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Ubiquitinas/metabolismo , Proteínas Culina/metabolismoRESUMO
OBJECTIVES: To discuss VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, including the clinical and pathologic features, diagnostic challenges, and treatment options. METHODS: A case-based approach and pertinent literature review were used to highlight the features of VEXAS syndrome, describe how to make the diagnosis, and discuss available therapies. RESULTS: VEXAS syndrome is an adult-onset, progressive systemic inflammatory disorder with overlapping rheumatologic and hematologic manifestations, including an increased risk of myelodysplastic neoplasms and plasma cell neoplasms. The disorder is associated with a somatic mutation of the X-linked UBA1 gene involved in ubiquitylation, typically involving p.Met41; however, rare variations have been identified outside this region. Patients often present with complex histories and see physicians from multiple specialties before receiving the diagnosis, which is often delayed. Symptoms are related to inflammation as well as cytopenias, particularly macrocytic anemia. Characteristic cytoplasmic vacuoles are present in myeloid (granulocytic, monocytic) and erythroid precursors in the vast majority of cases. CONCLUSIONS: Either clinicians or pathologists may suspect a diagnosis of VEXAS syndrome depending on the clinical presentation and bone marrow findings. More studies are needed to determine the best therapeutic options, which are currently limited.
Assuntos
Enzimas Ativadoras de Ubiquitina , Humanos , Enzimas Ativadoras de Ubiquitina/genética , Masculino , Vacúolos/patologia , Mutação , Pessoa de Meia-Idade , Síndrome , Inflamação/diagnósticoRESUMO
A 46-year-old male patient presented with inflammatory diseases over more than 3 years. The patient suffered from recurrent pleuritis, polychondritis, orbital phlegmon, fever, and skin lesions. A bone marrow puncture added myelodysplastic syndrome to the patient's history. A focused cytomorphological reinvestigation of the archived bone marrow aspirate smears detected significant vacuolization of erythroid and myeloid precursor cells. Target sequencing revealed the UBA1 (p.Met41Thr) hotspot mutation that established the diagnosis of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome.
Assuntos
Medula Óssea , Humanos , Masculino , Pessoa de Meia-Idade , Medula Óssea/patologia , Enzimas Ativadoras de Ubiquitina/genéticaRESUMO
BACKGROUND: VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by acquired somatic mutations in UBA1. Sweet-syndrome-like skin disorders [and especially histiocytoid Sweet syndrome (HSS)] may be associated with VEXAS syndrome. OBJECTIVES: To characterize the clinical and histopathological features of HSS in patients with VEXAS syndrome. METHODS: Skin biopsies with a histological diagnosis of HSS at Rennes University Medical Center (Rennes, France) between October 2011 and January 2022 were reviewed in this study. Sanger sequencing and digital polymerase chain reaction were used to screen skin, blood and bone marrow samples for UBA1 variants, and thus classify patients as having VEXAS syndrome or not. We evaluated the clinical, histological and molecular (UBA1) characteristics of patients with or without VEXAS syndrome. RESULTS: We compared 15 skin biopsies from 7 patients found to have VEXAS syndrome and 19 skin biopsies from 15 patients without VEXAS syndrome. Persistent C-reactive protein elevation, macrocytosis, anaemia and haematological malignancies were more prevalent in patients with VEXAS syndrome [6/7 (86%), 6/7 (86%), 7/7 (100%) and 6/7 (86%), respectively] than in patients without [5/14 (36%), 6/15 (40%), 8/15 (53%) and 8/15 (53%), respectively]. These features sometimes appeared after the first skin manifestations, and a UBA1 mutation was found in the skin of five patients with VEXAS syndrome. Dermal infiltration by reniform histiocytoid cells (myeloperoxidase-positive and/or CD163-positive) and a periadnexal distribution were more frequently observed in VEXAS syndrome biopsies [15/15 (100%) and 3/15 (20%), respectively, vs. 11/19 (58%) and 0/19 (0%) in non-VEXAS syndrome biopsies, respectively]. CONCLUSIONS: Our findings might help pathologists to consider a diagnosis of VEXAS syndrome and to initiate early genetic testing.
Assuntos
Mutação , Pele , Síndrome de Sweet , Enzimas Ativadoras de Ubiquitina , Humanos , Síndrome de Sweet/patologia , Síndrome de Sweet/genética , Masculino , Pessoa de Meia-Idade , Feminino , Biópsia , Enzimas Ativadoras de Ubiquitina/genética , Pele/patologia , Adulto , Idoso , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/patologia , Doenças Hereditárias Autoinflamatórias/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Doenças Genéticas Ligadas ao Cromossomo X/complicaçõesRESUMO
Helicobacter pylori (H. pylori) is a major risk factor of gastric cancer (GC). The SUMO-activating enzyme SAE1(SUMO-activating enzyme subunit 1), which is indispensable for protein SUMOylation, involves in human tumorigenesis. In this study, we used the TIMER and TCGA database to explore the SAE1 expression in GC and normal tissues and Kaplan-Meier Plotter platform for survival analysis of GC patients. GC tissue microarray and gastric samples from patients who underwent endoscopic treatment were employed to detect the SAE1expression. Our results showed that SAE1 was overexpressed in GC tissues and higher SAE1 expression was associated with worse clinical characteristics of GC patients. Cell and animal models showed that H. pylori infection upregulated SAE1, SUMO1, and SUMO2/3 protein expression. Functional assays suggested that suppression of SAE1 attenuated epithelial-mesenchymal transition (EMT) biomarkers and cell proliferation abilities induced by H. pylori. Cell and animal models of ROS inhibition in H. pylori showed that ROS could mediate the H. pylori-induced upregulation of SAE1, SUMO1, and SUMO2/3 protein. RNA sequencing was performed and suggested that knockdown of SAE1 could exert an impact on IGF-1 expression. General, increased SUMOylation modification is involved in H. pylori-induced GC.