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1.
Blood ; 126(4): 508-19, 2015 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-26082451

RESUMEN

The pathogenesis of mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is unknown. Although genetic alterations have been identified, none are considered consistently causative in MF. To identify potential drivers of MF, we performed whole-genome sequencing of MF tumors and matched normal skin. Targeted ultra-deep sequencing of MF samples and exome sequencing of CTCL cell lines were also performed. Multiple mutations were identified that affected the same pathways, including epigenetic, cell-fate regulation, and cytokine signaling, in MF tumors and CTCL cell lines. Specifically, interleukin-2 signaling pathway mutations, including activating Janus kinase 3 (JAK3) mutations, were detected. Treatment with a JAK3 inhibitor significantly reduced CTCL cell survival. Additionally, the mutation data identified 2 other potential contributing factors to MF, ultraviolet light, and a polymorphism in the tumor suppressor p53 (TP53). Therefore, genetic alterations in specific pathways in MF were identified that may be viable, effective new targets for treatment.


Asunto(s)
Exoma/genética , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación/genética , Micosis Fungoide/genética , Oncogenes/genética , Análisis de Secuencia de ADN/métodos , Neoplasias Cutáneas/genética , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Micosis Fungoide/patología , Micosis Fungoide/terapia , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Rayos Ultravioleta
2.
J Invest Dermatol ; 134(4): 1101-1107, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24304814

RESUMEN

The pathogenesis of the cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF), is unclear. MicroRNA (miRNA) are small noncoding RNAs that target mRNA leading to reduced mRNA translation. Recently, specific miRNA were shown to be altered in CTCL. We detected significantly reduced expression of miR-223 in early-stage MF skin, and further decreased levels of miR-223 in advanced-stage disease. CTCL peripheral blood mononuclear cells and cell lines also had reduced miR-223 as compared with controls. Elevated expression of miR-223 in these cell lines reduced cell growth and clonogenic potential, whereas inhibition of miR-223 increased cell numbers. Investigations into putative miR-223 targets with oncogenic function, including E2F1 and MEF2C, and the predicted miR-223 target, TOX, revealed that all three were targeted by miR-223 in CTCL. E2F1, MEF2C, and TOX proteins were decreased with miR-223 overexpression, whereas miR-223 inhibition led to increased protein levels in CTCL. In addition, we showed that the 3'-UTR of TOX mRNA was a genuine target of miR-223. Therefore, reduced levels of miR-223 in MF/CTCL lead to increased expression of E2F1, MEF2C, and TOX, which likely contributes to the development and/or progression of CTCL. Thus, miR-223 and its targets may be useful for the development of new therapeutics for MF/CTCL.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Linfoma Cutáneo de Células T/genética , Linfoma Cutáneo de Células T/metabolismo , MicroARNs/metabolismo , Micosis Fungoide/genética , Micosis Fungoide/metabolismo , Regiones no Traducidas 3' , Animales , Biopsia , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Ratones , Células 3T3 NIH , Proto-Oncogenes , Piel/patología
3.
Diabetes ; 59(10): 2662-71, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20622168

RESUMEN

OBJECTIVE: Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal. RESEARCH DESIGN AND METHODS: We genotyped 9,532 normal FPG participants (FPG <6.1 mmol/l) for three G6PC2 SNPs, rs13431652 (distal promoter), rs573225 (proximal promoter), rs560887 (3rd intron). We used regression analyses adjusted for age, sex, and BMI to assess the association with FPG and haplotype analyses to assess comparative SNP contributions. Fusion gene and gel retardation analyses characterized the effect of rs13431652 and rs573225 on G6PC2 promoter activity and transcription factor binding. RESULTS: Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652: ß = 0.075, P = 3.6 × 10(-35); rs573225 ß = 0.073 P = 3.6 × 10(-34)), in addition to rs560887 (ß = 0.071, P = 1.2 × 10(-31)). The rs13431652-A and rs573225-A alleles promote increased NF-Y and Foxa2 binding, respectively. The rs13431652-A allele is associated with increased FPG and elevated promoter activity, consistent with the function of G6PC2 in pancreatic islets. In contrast, the rs573225-A allele is associated with elevated FPG but reduced promoter activity. CONCLUSIONS: Genetic and in situ functional data support a potential role for rs13431652, but not rs573225, as a causative SNP linking G6PC2 to variations in FPG, though a causative role for rs573225 in vivo cannot be ruled out.


Asunto(s)
Ayuno , Glucosa-6-Fosfatasa/genética , Síndrome Metabólico/genética , Regiones Promotoras Genéticas , Adulto , Glucemia/genética , Niño , Estudios de Cohortes , Cartilla de ADN , Femenino , Finlandia/epidemiología , Regulación de la Expresión Génica , Variación Genética , Humanos , Resistencia a la Insulina/genética , Intrones/genética , Madres , Especificidad de Órganos , Polimorfismo de Nucleótido Simple , ARN/genética , ARN/aislamiento & purificación , Valores de Referencia , Población Blanca/genética
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