RESUMEN
DNA methylation is a fundamental epigenetic modification, important across biological processes. The maintenance methyltransferase DNMT1 is essential for lineage differentiation during development, but its functions in tissue homeostasis are incompletely understood. We show that epidermis-specific DNMT1 deletion severely disrupts epidermal structure and homeostasis, initiating a massive innate immune response and infiltration of immune cells. Mechanistically, DNA hypomethylation in keratinocytes triggered transposon derepression, mitotic defects, and formation of micronuclei. DNA release into the cytosol of DNMT1-deficient keratinocytes activated signaling through cGAS and STING, thus triggering inflammation. Our findings show that disruption of a key epigenetic mark directly impacts immune and tissue homeostasis, and potentially impacts our understanding of autoinflammatory diseases and cancer immunotherapy.
Asunto(s)
Metilación de ADN , Dermatitis/genética , Epidermis/fisiopatología , Nucleotidiltransferasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Aberraciones Cromosómicas , Citosol/fisiología , ADN (Citosina-5-)-Metiltransferasa 1/genética , Dermatitis/inmunología , Dermatitis/patología , Humanos , Inmunidad Innata/genética , Helicasa Inducida por Interferón IFIH1/metabolismo , Queratinocitos/inmunología , Queratinocitos/metabolismo , Queratinocitos/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Transgénicos , Nucleotidiltransferasas/genéticaRESUMEN
Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPß and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPß and SOCS1. In murine engraftment models of ALCL ALK(-), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPß target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1).
Asunto(s)
Cromosomas Humanos Par 2 , Cromosomas Humanos Par 5 , Linfoma Anaplásico de Células Grandes/genética , MicroARNs/genética , Translocación Genética , Quinasa de Linfoma Anaplásico , Animales , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/genética , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Estudios de Casos y Controles , Caspasa 3/metabolismo , Línea Celular Tumoral , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Terapia Genética/métodos , Humanos , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patología , Linfoma Anaplásico de Células Grandes/terapia , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/metabolismo , Regiones Promotoras Genéticas , Proteínas Tirosina Quinasas Receptoras/deficiencia , Proteínas Tirosina Quinasas Receptoras/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
(1) Background: Gastric carcinoma is an exceptionally rare tumor in childhood. Little is known about the etiology, epidemiology, and clinical features of pediatric gastric carcinomas. This analysis aimed to fill this gap by increasing knowledge about the occurrence of gastric carcinoma in childhood. (2) Material and methods: Data from gastric carcinoma cases diagnosed between 2000 and 2017/2018 were retrieved from the Surveillance, Epidemiology, and End Results Program (SEER) and the German Center for Cancer Registry Data. Data from patients <20 years of age were analyzed for patient- and tumor-related characteristics. In addition, clinical data from patients with gastric carcinoma registered in the German Registry for Rare Pediatric Tumors (STEP) were analyzed for diagnostics, therapy, and outcome. (3) Results: Ninety-one cases of gastric carcinoma, mainly in adolescents, were identified in the epidemiologic cancer registries. Among patients with recorded staging data, advanced tumor stages were common (66.7%). Within the follow-up period covered, 63.7% of patients with clinical follow-up data died. Eight pediatric patients with gastric carcinoma were enrolled in the STEP registry, among whom two were patients with hereditary CDH1 mutations and another was a patient with Peutz−Jeghers syndrome. Three patients were found to have distinctly decreased immunoglobulin concentrations. All four patients in whom complete resection was achieved remained in remission. Three of the other four patients died despite multimodal therapy. (4) Conclusions: A combination of Helicobacter pylori infection and tumor predisposition and/or immunodeficiency appears to promote the development of gastric carcinoma in childhood. While patients with localized disease stages have a good chance of achieving durable remission through complete resection, patients with stage IV carcinomas face a dismal prognosis, highlighting the need to develop new strategies such as mutation-guided treatments.