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1.
Nat Commun ; 11(1): 6318, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298918

RESUMO

Primary effusion lymphoma (PEL) has a very poor prognosis. To evaluate the contributions of enhancers/promoters interactions to PEL cell growth and survival, here we produce H3K27ac HiChIP datasets in PEL cells. This allows us to generate the PEL enhancer connectome, which links enhancers and promoters in PEL genome-wide. We identify more than 8000 genomic interactions in each PEL cell line. By incorporating HiChIP data with H3K27ac ChIP-seq data, we identify interactions between enhancers/enhancers, enhancers/promoters, and promoters/promoters. HiChIP further links PEL super-enhancers to PEL dependency factors MYC, IRF4, MCL1, CCND2, MDM2, and CFLAR. CRISPR knock out of MEF2C and IRF4 significantly reduces MYC and IRF4 super-enhancer H3K27ac signal. Knock out also reduces MYC and IRF4 expression. CRISPRi perturbation of these super-enhancers by tethering transcription repressors to enhancers significantly reduces target gene expression and reduces PEL cell growth. These data provide insights into PEL molecular pathogenesis.


Assuntos
Elementos Facilitadores Genéticos/genética , Redes Reguladoras de Genes , Linfoma de Efusão Primária/genética , Regiões Promotoras Genéticas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sequenciamento de Cromatina por Imunoprecipitação , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Herpesvirus Humano 8/patogenicidade , Histonas/genética , Humanos , Fatores Reguladores de Interferon/genética , Linfoma de Efusão Primária/patologia , Linfoma de Efusão Primária/virologia , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética
2.
Nat Commun ; 11(1): 6175, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268821

RESUMO

To elucidate the effects of neoadjuvant chemotherapy (NAC), we conduct whole transcriptome profiling coupled with histopathology analyses of a longitudinal breast cancer cohort of 146 patients including 110 pairs of serial tumor biopsies collected before treatment, after the first cycle of treatment and at the time of surgery. Here, we show that cytotoxic chemotherapies induce dynamic changes in the tumor immune microenvironment that vary by subtype and pathologic response. Just one cycle of treatment induces an immune stimulatory microenvironment harboring more tumor infiltrating lymphocytes (TILs) and up-regulation of inflammatory signatures predictive of response to anti-PD1 therapies while residual tumors are immune suppressed at end-of-treatment compared to the baseline. Increases in TILs and CD8+ T cell proportions in response to NAC are independently associated with pathologic complete response. Further, on-treatment immune response is more predictive of treatment outcome than immune features in paired baseline samples although these are strongly correlated.


Assuntos
Antígeno B7-H1/genética , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Terapia Neoadjuvante/métodos , Antraciclinas/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/mortalidade , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/imunologia , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Docetaxel/uso terapêutico , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imunidade Inata , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Estudos Longitudinais , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Neoplasia Residual , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Trastuzumab/uso terapêutico , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
3.
Nat Commun ; 11(1): 5637, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33159073

RESUMO

Antigen (Ag)-presenting cells (APC) instruct CD4+ helper T (Th) cell responses, but it is unclear whether different APC subsets contribute uniquely in determining Th differentiation in pathogen-specific settings. Here, we use skin-relevant, fluorescently-labeled bacterial, helminth or fungal pathogens to track and characterize the APC populations that drive Th responses in vivo. All pathogens are taken up by a population of IRF4+ dermal migratory dendritic cells (migDC2) that similarly upregulate surface co-stimulatory molecules but express pathogen-specific cytokine and chemokine transcripts. Depletion of migDC2 reduces the amount of Ag in lymph node and the development of IFNγ, IL-4 and IL-17A responses without gain of other cytokine responses. Ag+ monocytes are an essential source of IL-12 for both innate and adaptive IFNγ production, and inhibit follicular Th cell development. Our results thus suggest that Th cell differentiation does not require specialized APC subsets, but is driven by inducible and pathogen-specific transcriptional programs in Ag+ migDC2 and monocytes.


Assuntos
Fatores Reguladores de Interferon/imunologia , Monócitos/imunologia , Pele/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Diferenciação Celular , Células Dendríticas/imunologia , Feminino , Fatores Reguladores de Interferon/genética , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Linfócitos T Auxiliares-Indutores/citologia
4.
Pathologe ; 41(6): 574-581, 2020 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-32909092

RESUMO

The introduction of new lymphoma entities that are defined by chromosomal rearrangements has led to changes concerning the diagnostic algorithms in routine hematopathology, particularly for the large group of aggressive B­cell lymphomas. The new, genetically defined entity high-grade B­cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double/triple hit lymphoma) is morphologically heterogenous and comprises lymphomas with the morphology of a diffuse large B­cell lymphoma (DLBCL), but also cases with blastoid appearance as well as intermediate/Burkitt-like morphology. This implies a cytogenetic analysis for the final classification of aggressive lymphomas with DLBCL morphology, which constitute the most common lymphomas in daily practice. This analysis is currently most efficiently performed via a sequential fluorescence in situ hybridization (FISH) approach, with an initial MYC-FISH, that is followed (if required, i.e., if a MYC rearrangement is detected) by an analysis regarding a BCL2- and BCL6-chromosomal rearrangement. In addition, the update of the fourth edition of the WHO classification for hematopoietic neoplasms introduced additional lymphoma subgroups that are defined by chromosomal rearrangements, such as Burkitt-like lymphoma with 11q aberration as well as large B cell lymphoma with IRF4 rearrangement. Therefore, FISH currently plays an important role in the diagnostic armamentarium in routine diagnostic hematopathology.


Assuntos
Linfoma de Burkitt/diagnóstico , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma de Burkitt/genética , Aberrações Cromossômicas , Humanos , Fatores Reguladores de Interferon/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Translocação Genética
5.
Sci Data ; 7(1): 314, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963239

RESUMO

Establishing consensus around the transcriptional interface between coronavirus (CoV) infection and human cellular signaling pathways can catalyze the development of novel anti-CoV therapeutics. Here, we used publicly archived transcriptomic datasets to compute consensus regulatory signatures, or consensomes, that rank human genes based on their rates of differential expression in MERS-CoV (MERS), SARS-CoV-1 (SARS1) and SARS-CoV-2 (SARS2)-infected cells. Validating the CoV consensomes, we show that high confidence transcriptional targets (HCTs) of MERS, SARS1 and SARS2 infection intersect with HCTs of signaling pathway nodes with known roles in CoV infection. Among a series of novel use cases, we gather evidence for hypotheses that SARS2 infection efficiently represses E2F family HCTs encoding key drivers of DNA replication and the cell cycle; that progesterone receptor signaling antagonizes SARS2-induced inflammatory signaling in the airway epithelium; and that SARS2 HCTs are enriched for genes involved in epithelial to mesenchymal transition. The CoV infection consensomes and HCT intersection analyses are freely accessible through the Signaling Pathways Project knowledgebase, and as Cytoscape-style networks in the Network Data Exchange repository.


Assuntos
Infecções por Coronavirus/genética , Transição Epitelial-Mesenquimal/genética , Pneumonia Viral/genética , Transcriptoma , Betacoronavirus , Ciclo Celular , Consenso , Replicação do DNA , Conjuntos de Dados como Assunto , Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Coronavírus da Síndrome Respiratória do Oriente Médio , Pandemias , Receptores de Progesterona , Vírus da SARS , Transdução de Sinais
6.
Zhonghua Bing Li Xue Za Zhi ; 49(10): 1003-1008, 2020 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-32992413

RESUMO

Objective: To study the clinicopathological features of large B-cell lymphoma (LBCL) with IRF4 rearrangement. Methods: Seven cases of LBCL with IRF4 rearrangement collected at the First Affiliated Hospital of Nanjing Medical University from November 2018 to October 2019 were evaluated by hematoxylin and eosin staining, immunohistochemistry and fluorescence in situ hybridization detection. The relevant literature was reviewed. Results: Four tumors were located in the tonsils, 2 tumors in the lymphoid nodes and one tumor in the adenoid.The patients were 3 males and 4 females patients with a median age of 24 years (range, 6 to 39 years).Microscopically, entirely follicular pattern was present in one case, entirely diffuse pattern in 2 cases, and follicular and diffuse pattern in other 4 cases. The tumor cells were medium to large in size and showed the morphology of centroblasts or blastoid cells with irregular nuclei, brisk mitotic activity in 3 cases and starry sky in 2 cases. All of the cases were positive for CD20, PAX-5, bcl-6, and MUM1 and had a Ki-67 index>80%, while CD10 and bcl-2 were positive in 3 cases. IRF4 gene rearrangement was identified in all cases and bcl-6 gene rearrangement in 2 cases. All patients presented with localized disease with clinical stage Ⅰ or Ⅱ, except one with stage Ⅳ at presentation and a new lesion in the mediastinum developed 8 months later. Conclusions: LBCL with IRF4 rearrangement is a clinicopathologically distinct entity. The observations reveal a broader spectrum of morphology and biological behaviors. The relationship between clinical stage and prognosis needs to be determined in more cases.


Assuntos
Fatores Reguladores de Interferon , Linfoma de Células B , Linfoma Folicular , Linfoma não Hodgkin , Adolescente , Adulto , Criança , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Fatores Reguladores de Interferon/genética , Masculino , Adulto Jovem
7.
Nat Rev Immunol ; 20(10): 585-586, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32788708
8.
J Virol ; 94(18)2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32759316

RESUMO

An entirely plasmid-based reverse genetics (RG) system was recently developed for rotavirus (RV), opening new avenues for in-depth molecular dissection of RV biology, immunology, and pathogenesis. Several improvements to further optimize the RG efficiency have now been described. However, only a small number of individual RV strains have been recovered to date. None of the current methods have supported the recovery of murine RV, impeding the study of RV replication and pathogenesis in an in vivo suckling mouse model. Here, we describe useful modifications to the RG system that significantly improve rescue efficiency of multiple RV strains. In addition to the 11 group A RV segment-specific (+)RNAs [(+)ssRNAs], a chimeric plasmid was transfected, from which the capping enzyme NP868R of African swine fever virus (ASFV) and the T7 RNA polymerase were expressed. Second, a genetically modified MA104 cell line was used in which several components of the innate immunity were degraded. Using this RG system, we successfully recovered the simian RV RRV strain, the human RV CDC-9 strain, a reassortant between murine RV D6/2 and simian RV SA11 strains, and several reassortants and reporter RVs. All these recombinant RVs were rescued at a high efficiency (≥80% success rate) and could not be reliably rescued using several recently published RG strategies (<20%). This improved system represents an important tool and great potential for the rescue of other hard-to-recover RV strains such as low-replicating attenuated vaccine candidates or low-cell culture passage clinical isolates from humans or animals.IMPORTANCE Group A rotavirus (RV) remains as the single most important cause of severe acute gastroenteritis among infants and young children worldwide. An entirely plasmid-based reverse genetics (RG) system was recently developed, opening new ways for in-depth molecular study of RV. Despite several improvements to further optimize the RG efficiency, it has been reported that current strategies do not enable the rescue of all cultivatable RV strains. Here, we described a helpful modification to the current strategies and established a tractable RG system for the rescue of the simian RRV strain, the human CDC-9 strain, and a murine-like RV strain, which is suitable for both in vitro and in vivo studies. This improved RV reverse genetics system will facilitate study of RV biology in both in vitro and in vivo systems that will facilitate the improved design of RV vaccines, better antiviral therapies, and expression vectors.


Assuntos
Regulação Viral da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Vírus Reordenados/genética , Genética Reversa/métodos , Rotavirus/genética , Proteínas Virais/genética , Vírus da Febre Suína Africana/genética , Vírus da Febre Suína Africana/imunologia , Animais , Chlorocebus aethiops , RNA Polimerases Dirigidas por DNA/genética , RNA Polimerases Dirigidas por DNA/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Camundongos , Nucleotidiltransferases/genética , Nucleotidiltransferases/imunologia , Plasmídeos/química , Plasmídeos/metabolismo , Capuzes de RNA , Vírus Reordenados/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Rotavirus/imunologia , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Transfecção , Células Vero , Proteínas Virais/imunologia , Replicação Viral
9.
Oncogene ; 39(41): 6406-6420, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32855526

RESUMO

DNA methylation is implicated in the acquisition of malignant phenotypes, and the use of epigenetic modulating drugs is a promising anti-cancer therapeutic strategy. 5-aza-2'deoxycytidine (decitabine, 5-azadC) is an FDA-approved DNA methyltransferase (DNMT) inhibitor with proven effectiveness against hematological malignancies and more recently triple-negative breast cancer (BC). Herein, genetic or pharmacological studies uncovered a hitherto unknown feedforward molecular link between DNMT1 and the estrogen related receptor α (ERRα), a key transcriptional regulator of cellular metabolism. Mechanistically, DNMT1 promotes ERRα stability which in turn couples DNMT1 transcription with that of the methionine cycle and S-adenosylmethionine synthesis to drive DNA methylation. In vitro and in vivo investigation using a pre-clinical mouse model of BC demonstrated a clear therapeutic advantage for combined administration of the ERRα inhibitor C29 with 5-azadC. A large-scale bisulfite genomic sequencing analysis revealed specific methylation perturbations fostering the discovery that reversal of promoter hypermethylation and consequently derepression of the tumor suppressor gene, IRF4, is a factor underlying the observed BC suppressive effects. This work thus uncovers a critical role of ERRα in the crosstalk between transcriptional control of metabolism and epigenetics and illustrates the potential for targeting ERRα in combination with DNMT inhibitors for BC treatment and other epigenetics-driven malignancies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , Fatores Reguladores de Interferon/genética , Receptores Estrogênicos/metabolismo , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ilhas de CpG/genética , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Decitabina/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , Estabilidade Proteica , Receptores Estrogênicos/antagonistas & inibidores , S-Adenosilmetionina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Sci Rep ; 10(1): 13094, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753663

RESUMO

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive subtype of lymphoma usually associated with inferior outcomes. ABC-DLBCL exhibits plasmablastic features and is characterized by aberrancies in the molecular networks controlled by IRF4. The signaling pathways that are dysregulated in ABC-DLBCL are, however, not fully understood. ROCK2 is a serine-threonine kinase whose role in lymphomagenesis is unknown. Here we show that ROCK2 activity is constitutively dysregulated in ABC-DLBCL but not in GCB-DLBCL and BL. We furthermore show that ROCK2 phosphorylates IRF4 and that the ROCK2-mediated phosphorylation of IRF4 modulates its ability to regulate a subset of target genes. In addition to its effects on IRF4, ROCK2 also controls the expression of MYC in ABC-DLBCL by regulating MYC protein levels. ROCK inhibition furthermore selectively decreases the proliferation and survival of ABC-DLBCL in vitro and inhibits ABC-DLBCL growth in xenograft models. Thus, dysregulated ROCK2 activity contributes to the aberrant molecular program of ABC-DLBCL via its dual ability to modulate both IRF4- and MYC-controlled gene networks and ROCK inhibition could represent an attractive therapeutic target for the treatment of ABC-DLBCL.


Assuntos
Redes Reguladoras de Genes , Linfoma Difuso de Grandes Células B/genética , Transcrição Genética , Quinases Associadas a rho/metabolismo , Linhagem Celular Tumoral , Humanos , Fatores Reguladores de Interferon/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-myc/metabolismo
11.
Oral Dis ; 26 Suppl 1: 165-168, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32862534

RESUMO

We present here the first reported case of a non-syndromic cleft lip and palate (NSCLP) in an HIV-exposed newborn of a mother on antiretroviral therapy (ART) in Indonesia. Genetic testing was performed to confirm a suspected genetic condition. Genomic DNA was extracted from the blood, and genetic variations of the interferon regulatory factor 6 (IRF6) rs642961 (Mspl) (G>A) and transforming growth factor alpha (TGFA) BamHI (rs11466297, A>C) and RsaI (rs3732248, C>T) were performed by PCR-RFLP and IRF6 gene analysis by PCR sequencing. Genotyping of DNA sequence variants in the IRF6 gene showed both parents had genotype GA, while the child had genotype GG (genotype wild type). There was no difference observed in the TGFA BamHI gene variant between the child and her mother and father that were wild-type polymorphisms (normal), while the Rsa1 polymorphisms of them were heterozygotes. A genetic variant of IRF6 might be a protective factor for NSCLP, while Rsa1 gene variant (A) allele can be considered to be the risk factor associated with NSCLP development. This case report also highlights the possible etiologic role of ART in NSCLP; therefore, early control of adverse effects of ART might be an important factor in decreasing the incidence of the congenital anomalies in HIV-infected children.


Assuntos
Fenda Labial , Fissura Palatina , Infecções por HIV , Fatores Reguladores de Interferon , Fator de Crescimento Transformador alfa , Antirretrovirais/uso terapêutico , Fenda Labial/genética , Fissura Palatina/genética , Feminino , Variação Genética/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Humanos , Recém-Nascido , Fatores Reguladores de Interferon/genética , Polimorfismo de Nucleotídeo Único , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Fator de Crescimento Transformador alfa/genética
12.
PLoS Pathog ; 16(8): e1008678, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760119

RESUMO

GWAS, immune analyses and biomarker screenings have identified host factors associated with in vivo HIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natural HIV-1 control. To this end, whole DNA methylome in 70 untreated HIV-1 infected individuals with either high (>50,000 HIV-1-RNA copies/ml, n = 29) or low (<10,000 HIV-1-RNA copies/ml, n = 41) plasma viral load (pVL) levels were compared and identified 2,649 differentially methylated positions (DMPs). Of these, a classification random forest model selected 55 DMPs that correlated with virologic (pVL and proviral levels) and HIV-1 specific adaptive immunity parameters (IFNg-T cell responses and neutralizing antibodies capacity). Then, cluster and functional analyses identified two DMP clusters: cluster 1 contained hypo-methylated genes involved in antiviral and interferon response (e.g. PARP9, MX1, and USP18) in individuals with high viral loads while in cluster 2, genes related to T follicular helper cell (Tfh) commitment (e.g. CXCR5 and TCF7) were hyper-methylated in the same group of individuals with uncontrolled infection. For selected genes, mRNA levels negatively correlated with DNA methylation, confirming an epigenetic regulation of gene expression. Further, these gene expression signatures were also confirmed in early and chronic stages of infection, including untreated, cART treated and elite controllers HIV-1 infected individuals (n = 37). These data provide the first evidence that host genes critically involved in immune control of the virus are under methylation regulation in HIV-1 infection. These insights may offer new opportunities to identify novel mechanisms of in vivo virus control and may prove crucial for the development of future therapeutic interventions aimed at HIV-1 cure.


Assuntos
Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Metilação de DNA , Infecções por HIV/imunologia , HIV-1/imunologia , Fatores Reguladores de Interferon/genética , Carga Viral , Antivirais/uso terapêutico , Epigênese Genética , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Interações Hospedeiro-Patógeno , Humanos , Fatores Reguladores de Interferon/metabolismo , Interferons/metabolismo , Masculino , Linfócitos T Auxiliares-Indutores/imunologia , Replicação Viral
13.
PLoS Pathog ; 16(8): e1008730, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776977

RESUMO

Kaposi's sarcoma (KS), caused by Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angioproliferative disseminated tumor of endothelial cells commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) mediates KSHV-induced cell motility (PLoS Pathog. 2019 Jan 30;15(1):e1007578). However, the role of vIRF1 in KSHV-induced cellular transformation and angiogenesis remains unknown. Here, we show that vIRF1 promotes angiogenesis by upregulating sperm associated antigen 9 (SPAG9) using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice. Mechanistically, vIRF1 interacts with transcription factor Lef1 to promote SPAG9 transcription. vIRF1-induced SPAG9 promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with JNK1/2 to increase their phosphorylation, resulting in enhanced VEGFA expression, angiogenesis, cell proliferation and migration. Finally, genetic deletion of ORF-K9 from KSHV genome abolishes KSHV-induced cellular transformation and impairs angiogenesis. Our results reveal that vIRF1 transcriptionally activates SPAG9 expression to promote angiogenesis and tumorigenesis via activating JNK/VEGFA signaling. These novel findings define the mechanism of KSHV induction of the SPAG9/JNK/VEGFA pathway and establish the scientific basis for targeting this pathway for treating KSHV-associated cancers.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Herpesvirus Humano 8/metabolismo , Fatores Reguladores de Interferon/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Sarcoma de Kaposi/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Virais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Transformação Celular Neoplásica , Herpesvirus Humano 8/genética , Interações Hospedeiro-Patógeno , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/genética , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/fisiopatologia , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/fisiopatologia , Sarcoma de Kaposi/virologia , Fator A de Crescimento do Endotélio Vascular/genética , Proteínas Virais/genética
14.
Cancer Genet ; 245: 6-16, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32535543

RESUMO

In mature B-cell malignancies, chromosomal translocations often juxtapose an oncogenic locus to the regulatory regions of the immunoglobulin genes. These genomic rearrangements can associate with specific clinical/pathological sub-entities and inform diagnosis and treatment decisions. Recently, we characterized the t(14;16)(q32;q24) in diffuse large B-cell lymphoma (DLBCL), and showed that it targets the transcription factor IRF8, which is also somatically mutated in ~10% of DLBCLs. IRF8 regulates innate and adaptive immune responses mediated by myeloid/monocytic and lymphoid cells. While the role of IRF8 in human myeloid/dendritic-cell disorders is well established, less is known of its contribution to the pathogenesis of mature B-cell malignancies. To address this knowledge gap, we generated the Eµ-Irf8 mouse model, which mimics the IRF8 deregulation associated with t(14;16) of DLBCL. Eµ-Irf8 mice develop normally and display peripheral blood cell parameters within normal range. However, Eµ-Irf8 mice accumulate pre-pro-B-cells and transitional B-cells in the bone marrow and spleen, respectively, suggesting that the physiological role of Irf8 in B-cell development is amplified. Notably, in Eµ-Irf8 mice, the lymphomagenic Irf8 targets Aicda and Bcl6 are overexpressed in mature B-cells. Yet, the incidence of B-cell lymphomas is not increased in the Eµ-Irf8 model, even though their estimated survival probability is significantly lower than that of WT controls. Together, these observations suggest that the penetrance on the Irf8-driven phenotype may be incomplete and that introduction of second genetic hit, a common strategy in mouse models of lymphoma, may be necessary to uncover the pro-lymphoma phenotype of the Eµ-Irf8 mice.


Assuntos
Cadeias Pesadas de Imunoglobulinas/genética , Fatores Reguladores de Interferon/genética , Linfoma de Células B/mortalidade , Proteínas de Fusão Oncogênica/genética , Animais , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Feminino , Humanos , Linfoma de Células B/genética , Masculino , Camundongos , Análise de Sobrevida
15.
Reprod Sci ; 27(10): 1857-1862, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32533457

RESUMO

The aim of this study was to assess the association between IRF6 single nucleotide polymorphisms and nonsyndromic cleft lip, with or without cleft palate (NSCL/P), in a Chilean population, based on a case-control sample and confirmed in a case-parent trio population. In a sample of 150 Chilean case-parent trios and 164 controls (cohort 1), we evaluated the association between three common IRF6 variants (rs764093, rs2236909, rs2235375) and NSCL/P using odds ratio (OR) for case-control and case-parent trios and in a combined OR of both designs. To confirm associations from the cohort 1, we increased the sample size to 215 triads and 320 controls (cohort 1 + cohort 2). The combined OR for the cohort 1 reveals that the rs2235375 C allele is associated with NSCL/P in Chile (OR 1.34; p = 0.013), which was supported by the results for the two cohorts (OR 1.29; p = 0.006). Bioinformatic prediction showed that this variant, located 27 bp downstream from IRF6 exon 6, potentially alters the splicing process and based on functional annotations is associated with a decrease of gene expression. We propose that the C allele of rs2235375 from IRF6 gene seems to be a risk factor for NSCL/P in a Chilean population. However, we cannot discard a population stratification bias in our findings. On the other hand, further studies are necessary to confirm the biological role of rs2235375 in IRF6 function at craniofacial development level.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Fatores Reguladores de Interferon/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Chile , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino
16.
Sci Rep ; 10(1): 9239, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514046

RESUMO

Despite the advantages of neoadjuvant chemotherapy (NACT), associated toxicity is a serious complication that renders monitoring of the patients' response to NACT highly important. Thus, prediction of tumor response to treatment is imperative to avoid exposure of potential non-responders to deleterious complications. We have performed genome-wide analysis of DNA methylation by XmaI-RRBS and selected CpG dinucleotides differential methylation of which discriminates luminal B breast cancer samples with different sensitivity to NACT. With this data, we have developed multiplex methylation sensitive restriction enzyme PCR (MSRE-PCR) protocol for determining the methylation status of 10 genes (SLC9A3, C1QL2, DPYS, IRF4, ADCY8, KCNQ2, TERT, SYNDIG1, SKOR2 and GRIK1) that distinguish BC samples with different NACT response. Analysis of these 10 markers by MSRE-PCR in biopsy samples allowed us to reveal three top informative combinations of markers, (1) IRF4 and C1QL2; (2) IRF4, C1QL2, and ADCY8; (3) IRF4, C1QL2, and DPYS, with the areas under ROC curves (AUCs) of 0.75, 0.78 and 0.74, respectively. A classifier based on IRF4 and C1QL2 better meets the diagnostic panel simplicity requirements, as it consists of only two markers. Diagnostic accuracy of the panel of these two markers is 0.75, with the sensitivity of 75% and specificity of 75%.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Metilação de DNA , Terapia Neoadjuvante , Área Sob a Curva , Neoplasias da Mama/patologia , Ilhas de CpG , Feminino , Humanos , Fatores Reguladores de Interferon/genética , Canal de Potássio KCNQ2/genética , Modelos Logísticos , Pessoa de Meia-Idade , Curva ROC , Trocador 3 de Sódio-Hidrogênio/genética
17.
Gene ; 753: 144814, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32464244

RESUMO

AIMS: The goal of our study is to investigate the contribution of the 13 single-nucleotide polymorphisms to inflammatory bowel disease (IBD), including Crohn's disease (CD) and Ulcerative colitis (UC). METHODS: A total of 44 articles were retrieved from bibliographic databases including PubMed, Embase, SpingerLink, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang. Through a comprehensive filtering procedure, 13 single-nucleotide polymorphisms were collected in the meta-analysis, which was done by Review Manager 5.0. RESULTS: After a systematic filtration, there were 13 single-nucleotide polymorphisms (SNPs) from 44 articles involved in our meta-analysis. Our results demonstrated that 3 SNPs were found to be significantly associated with CD/UC/IBD: IRF5 rs4728142 (UC: OR = 1.21, 95% CI = 1.09-1.35, P = 0.0003; OR = 1.30, 95% CI = 1.08-1.57, P = 0.006 in Asian), PTGER4 rs4613763 (CD: the overall OR = 1.28, 95% CI = 1.01-1.64, P = 0.04; IBD: OR = 1.31, 95% CI = 1.04-1.65, P = 0.02), IL12B rs6887695 (CD: the overall OR = 1.17, 95% CI = 1.06-1.30, P = 0.002; UC: the overall OR = 1.13, 95% CI = 1.01-1.26, P = 0.03; IBD: the overall OR = 1.15, 95% CI = 1.06-1.24, P = 0.0009). CONCLUSION: Our meta-analyses have indicated the significant associations between SNPs (IRF5 rs4728142, PTGER4 rs4613763, and IL12B rs6887695) and CD/UC/IBD.


Assuntos
Doenças Inflamatórias Intestinais/genética , Fatores Reguladores de Interferon/genética , Subunidade p40 da Interleucina-12/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Colite Ulcerativa/genética , Doença de Crohn/genética , Suscetibilidade a Doenças , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
18.
Clin Exp Rheumatol ; 38 Suppl 124(2): 182-187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32441646

RESUMO

OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a major regulator of type I interferon induction and is also critical to produce pro-inflammatory cytokines. An influence of IRF5 genetic variants on the increased risk of immune-mediated diseases has been described. Accordingly, we aimed to evaluate the implication of IRF5 in the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. METHODS: Three tag genetic variants (rs2004640, rs2070197 and rs10954213), representative of 3 different haplotype blocks within IRF5, were genotyped in 372 Caucasian patients with IgAV and 876 sex and ethnically matched healthy controls by TaqMan assays. RESULTS: No significant differences in the genotype and allele frequencies between patients with IgAV and healthy controls were observed when each IRF5 polymorphism was evaluated independently. Likewise, no significant differences between patients with IgAV and healthy controls were found when we assessed the three IRF5 polymorphisms combined, conforming haplotypes. In addition, there were no significant differences in genotype, allele and haplotype frequencies of IRF5 when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IRF5 on the pathogenesis of IgAV.


Assuntos
Predisposição Genética para Doença , Imunoglobulina A , Fatores Reguladores de Interferon/genética , Vasculite/genética , Estudos de Casos e Controles , Genótipo , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único
19.
Clin Immunol ; 215: 108410, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-38673

RESUMO

Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.


Assuntos
Infecções por Coronavirus/genética , Epigênese Genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Viremia/genética , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Antígeno CD11a/genética , Antígeno CD11a/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/imunologia , Metilação de DNA , Progressão da Doença , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Estresse Oxidativo/genética , Estresse Oxidativo/imunologia , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Ligação Proteica , Receptores KIR/genética , Receptores KIR/imunologia , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Viremia/complicações , Viremia/epidemiologia , Viremia/imunologia
20.
Cancer Res ; 80(13): 2927-2939, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32341037

RESUMO

In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer but decreased in CRPC compared with normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and enzalutamide resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated prostate cancer progression and enzalutamide resistance in vitro and in vivo. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targeting the IRF8-AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in prostate cancer pathogenesis and a potential alternative therapeutic option to overcome enzalutamide resistance. SIGNIFICANCE: These findings identify IRF8-mediated AR degradation as a mechanism of resistance to AR-targeted therapy, highlighting the therapeutic potential of IFNα in targeting IRF8-AR axis in CRPC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2927/F1.large.jpg.


Assuntos
Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Retroalimentação Fisiológica , Fatores Reguladores de Interferon/metabolismo , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Idoso de 80 Anos ou mais , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Feniltioidantoína/farmacologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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