RESUMEN
Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies in adults. The tumor microenvironment (TME) has a critical effect on AML occurrence, recurrence, and progression. The gene feline leukemia virus subgroup C cellular receptor family member 2 (FLVCR2) belongs to the major facilitator superfamily of transporter protein members, which is primarily involved in transporting small molecules. The potential role of FLVCR2 in the TME in AML has not been investigated. To clarify the expression and role of FLVCR2 in AML, we analyzed the Gene Expression Omnibus and The Cancer Genome Atlas databases and found that FLVCR2 mRNA expression significantly increased among patients with AML. Furthermore, based on an analysis of the Gene Expression Profiling Interactive Analysis database, FLVCR2 upregulation predicted dismal overall survival of patients with AML. Our validation analysis revealed the significant upregulation of FLVCR2 within the bone marrow of AML relative to healthy controls by western blotting and qPCR assays. Gene set enrichment analysis was conducted to explore FLVCR2's related mechanism in AML. We found that high FLVCR2 expression was related to infiltration degrees of immune cells and immune scores among AML cases, indicating that FLVCR2 possibly had a crucial effect on AML progression through the immune response. Specifically, FLVCR2 upregulation was negatively related to the immune infiltration degrees of activated natural killer cells, activated memory CD4+ T cells, activated dendritic cells, and CD8+ T cells using CIBERSORT analysis. According to the in vitro research, FLVCR2 silencing suppressed AML cell growth and promoted their apoptosis. This study provides insights into FLVCR2's effect on tumor immunity, indicating that it might serve as an independent prognostic biomarker and was related to immune infiltration within AML.
RESUMEN
Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder of brain angiogenesis. PVHH has long been considered to be prenatally lethal. We evaluated the phenotypes of the first three siblings with survival into adulthood, performed a systematic review of the Fowler syndrome literature and delineated genotype-phenotype correlations using a scoring system to rate the severity of the disease. Thirty articles were included, describing 69 individual patients. To date, including our clinical reports, 72 patients have been described with Fowler syndrome. Only 6/72 (8%) survived beyond birth. Although our three patients carry the same mutations (c.327T>A-p.Asn109Lys and c.887C>T-p.Ser296Leu) in FLVCR2, only two of them presented with the same cerebral features, ventriculomegaly and cerebral calcifications, as affected fetuses. The third sibling has a surprisingly milder clinical and radiological phenotype, suggesting intrafamilial variability. Although no clear phenotype-genotype correlation exists, some variants appear to be associated with a less severe phenotype compatible with life. As such, it is important to consider Fowler syndrome in patients with gross ventriculomegaly, cortical malformations and/or cerebral calcifications on brain imaging.
Asunto(s)
Hidranencefalia/genética , Proteínas de Transporte de Membrana/genética , Neovascularización Patológica/genética , Receptores Virales/genética , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Asociación Genética , Humanos , Hidranencefalia/patología , Mutación/genética , Neovascularización Patológica/patología , FenotipoRESUMEN
The feline leukemia virus subgroup C receptors (FLVCRs) were originally cloned as virus receptors, but are now believed to function also as heme transporters and are expressed in a broad range of tissues in a wide range of mammalian species. Expression of FLVCR1 and FLVCR2 was investigated in 19 bovine papillomavirus-associated urinary bladder cancers and in 15 non-neoplastic samples of bladder from cattle. E5 oncoprotein of bovine Deltapapillomaviruses (δPVs) was detected in 17 of the 19 bladder cancers. Flvcr1 and Flvcr2 were amplified and sequenced both in neoplastic and non-neoplastic samples showing a 100% identity with bovine Flvcr1 and Flvcr2 mRNA sequences present in GenBank database (accession numbers: NM_001206019.1 and NM_001192143.1, respectively). Reverse transcription (RT)-PCR showed that Flvcr1 and Flvcr2 were overexpressed in 4 and 5 out of 19 urothelial cancers, respectively, but in none of the non-neoplastic samples. In addition, western blot analysis detected higher levels of FLVCR1 and FLVCR2 in samples in which transcripts were not increased, suggesting post-translational changes to these proteins. Increased FLCVR1 and FLVCR2 was also observed immunohistochemically in the neoplastic cells. Immunolabeling for FLVCR1 was seen in the cytoplasm and plasm membrane of urothelial cancer cells, wheras immunolabeling for FLVCR2 was present within the nucleus. This is the first time that FLVCR expression has been investigated in bovine tissues and the first to suggest that expression could be increased in cancers. Additional studies are required to define the role, if any, of FLVCR in papillomavirus-associated cancer cells.
Asunto(s)
Papillomavirus Bovino 1 , Enfermedades de los Bovinos/virología , Proteínas de Transporte de Membrana/metabolismo , Receptores Virales/metabolismo , Neoplasias de la Vejiga Urinaria/veterinaria , Urotelio/metabolismo , Animales , Bovinos , Regulación Neoplásica de la Expresión Génica , Proteínas de Transporte de Membrana/genética , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/veterinaria , Infecciones por Papillomavirus/virología , Receptores Virales/genética , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/virologíaRESUMEN
BACKGROUND: Fowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly-hydrocephaly and multiple pterygium due to fetal akinesia. To date, around 45 cases from 27 families have been reported, and the pathogenic bi-allelic mutations in FLVCR2 gene described in 15 families. The pathogenesis of this condition has not been fully elucidated so far. METHODS: We report on an additional family with two affected fetuses carrying a novel homozygous mutation in FLVCR2 gene, and describe the impact of known mutants on the protein structural and functional impairment. RESULTS: The present report confirms the genetic homogeneity of Fowler syndrome and describes a new FLVCR2 mutation affecting the protein function. The structural analysis of the present and previously published FLVCR2 mutations supports the hypothesis of a reduced heme import as the underlying disease's mechanism due to the stabilization of the occluded conformation or a protein misfolding. CONCLUSION: Our data suggest the hypothesis of heme deficiency as the major pathogenic mechanism of Fowler syndrome.
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Hidranencefalia/genética , Proteínas de Transporte de Membrana/genética , Receptores Virales/genética , Alelos , Secuencia de Aminoácidos/genética , Feto/patología , Hemo/genética , Hemo/metabolismo , Humanos , Hidranencefalia/fisiopatología , Hidrocefalia/genética , Proteínas de Transporte de Membrana/fisiología , Mutación , Receptores Virales/fisiología , Enfermedades Vasculares/genéticaRESUMEN
Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder, caused by mutations in FLVCR2. Hallmarks of the syndrome are glomerular vasculopathy in the central nervous system, severe hydrocephaly, hypokinesia and arthrogryphosis. The disorder is considered prenatally lethal. We report the first patients, a brother and a sister, with Fowler syndrome and survival beyond infancy. The patients present a phenotype of severe intellectual and neurologic disability with seizures, absence of functional movements, and no means of communication. Imaging of the brain showed calcifications, profound ventriculomegaly with only a thin edging of the cerebral cortex and hypoplastic cerebellum. Investigation with whole-exome sequencing (WES) revealed, in both patients, a homozygous pathogenic mutation in FLVCR2, c.1289C>T, compatible with a diagnosis of Fowler syndrome. The results highlight the power of combining WES with a thorough clinical examination in order to identify disease-causing mutations in patients whose clinical presentation differs from previously described cases. Specifically, the findings demonstrate that Fowler syndrome is a diagnosis to consider, not only prenatally but also in severely affected children with gross ventriculomegaly on brain imaging.
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Hidranencefalia/diagnóstico , Hidranencefalia/genética , Hidrocefalia/diagnóstico , Hidrocefalia/genética , Proteínas de Transporte de Membrana/genética , Mutación , Receptores Virales/genética , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/genética , Alelos , Encéfalo , Preescolar , Análisis Mutacional de ADN , Exones , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Linaje , Fenotipo , Hermanos , SíndromeRESUMEN
BACKGROUND: Hydranencephaly is a relatively rare but severe structural brain abnormality that often results in perinatal death. Although several factors including infection and multiple births have been reported to be associated with this birth defect, the underlying etiology is not well understood. Recently, FLVCR2 gene mutations have been implicated in a subset of hydranencephaly cases, following an autosomal recessive pattern of inheritance. CASE: We report a male infant with hydranencephaly found to have a previously unreported six amino acid deletion in one copy of the FLVCR2 gene following a pregnancy complicated by poor prenatal care and maternal cocaine use. Although our patient currently presents with developmental delays, he is showing progress and gaining some skills. CONCLUSION: We discuss the possibility of a synergistic effect between the FLVCR2 genetic mutation and environmental cocaine exposure, creating a susceptible brain, as an explanation for this infant's phenotype. This case demonstrates the potential clinical utility of testing for mutations in FLVCR2 for patients with hydranencephaly after other possible etiologies, such as congenital infection, have been reasonably eliminated. Current literature on FLVCR2 is relatively sparse; identifying additional patients with similar mutations will aid in defining the clinical significance of a gene mutation and the contribution to the etiology of hydranencephaly.
Asunto(s)
Trastornos Relacionados con Cocaína/genética , Hidranencefalia/genética , Proteínas de Transporte de Membrana/genética , Mutación/genética , Efectos Tardíos de la Exposición Prenatal/genética , Receptores Virales/genética , Encéfalo/efectos de los fármacos , Encéfalo/patología , Trastornos Relacionados con Cocaína/patología , Femenino , Enfermedades Fetales/diagnóstico por imagen , Enfermedades Fetales/genética , Enfermedades Fetales/patología , Humanos , Hidranencefalia/patología , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Fenotipo , Embarazo , Eliminación de Secuencia , Ultrasonografía PrenatalRESUMEN
Heme (iron-protoporphyrin IX) is an essential co-factor involved in multiple biological processes: oxygen transport and storage, electron transfer, drug and steroid metabolism, signal transduction, and micro RNA processing. However, excess free-heme is highly toxic due to its ability to promote oxidative stress and lipid peroxidation, thus leading to membrane injury and, ultimately, apoptosis. Thus, heme metabolism needs to be finely regulated. Intracellular heme amount is controlled at multiple levels: synthesis, utilization by hemoproteins, degradation and both intracellular and intercellular trafficking. This review focuses on recent findings highlighting the importance of controlling intracellular heme levels to counteract heme-induced oxidative stress. The contributions of heme scavenging from the extracellular environment, heme synthesis and incorporation into hemoproteins, heme catabolism and heme transport in maintaining adequate intracellular heme content are discussed. Particular attention is put on the recently described mechanisms of heme trafficking through the plasma membrane mediated by specific heme importers and exporters. Finally, the involvement of genes orchestrating heme metabolism in several pathological conditions is illustrated and new therapeutic approaches aimed at controlling heme metabolism are discussed.