RESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) frequently involves aberrant expression of TAL1 (T-cell acute lymphocytic leukemia 1) and LMO2, oncogenic members of the TAL1 transcriptional complex. Transcriptional activity of the TAL1-complex is thought to have a pivotal role in the transformation of thymocytes and is associated with a differentiation block and self-renewal. The transcription factor Forkhead Box P3 (FOXP3) was recently described to be expressed in a variety of malignancies including T-ALL. Here we show that increased FOXP3 levels negatively correlate with expression of genes regulated by the oncogenic TAL1-complex in human T-ALL patient samples as well as a T-ALL cell line ectopically expressing FOXP3. In these cells, FOXP3 expression results in altered regulation of cell cycle progression and reduced cell viability. Finally, we demonstrate that FOXP3 binds LMO2 in vitro, resulting in decreased interaction between LMO2 and TAL1, providing a molecular mechanism for FOXP3-mediated transcriptional modulation in T-ALL. Collectively, our findings provide initial evidence for a novel role of FOXP3 as a tumor suppressor in T-ALL through modulation of TAL1 transcriptional activity.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción Forkhead/fisiología , Proteínas con Dominio LIM/fisiología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/fisiología , Ciclo Celular , Factores de Transcripción Forkhead/análisis , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteína 1 de la Leucemia Linfocítica T Aguda , Proteínas Supresoras de Tumor/fisiologíaRESUMEN
The transcription factor T-cell acute lymphocytic leukemia (TAL)-1 is a major T-cell oncogene associated with poor prognosis in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 binds histone deacetylase 1 and incubation with histone deacetylase inhibitors (HDACis) promotes apoptosis of leukemia cells obtained from TAL1 transgenic mice. Here, we show for the first time that TAL1 protein expression is strikingly downregulated upon histone deacetylase inhibition in T-ALL cells. This is due to decreased TAL1 gene transcription in cells with native TAL1 promoter, and due to impaired TAL1 mRNA translation in cells that harbor the TAL1(d) microdeletion and consequently express TAL1 under the control of the SCL/TAL1 interrupting locus (SIL) promoter. Notably, HDACi-triggered apoptosis of T-ALL cells is significantly reversed by TAL1 forced overexpression. Our results indicate that the HDACi-mediated apoptotic program in T-ALL cells is partially dependent on their capacity to downregulate TAL1 and provide support for the therapeutic use of HDACi in T-ALL.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Regulación hacia Abajo , Inhibidores de Histona Desacetilasas/farmacología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Regulación hacia Arriba , Inmunoprecipitación de Cromatina , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteína 1 de la Leucemia Linfocítica T Aguda , Células Tumorales CultivadasRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is a biologically heterogeneous disease with respect to phenotype, gene expression profile and activation of particular intracellular signaling pathways. Despite very significant improvements, current therapeutic regimens still fail to cure a portion of the patients and frequently implicate the use of aggressive protocols with long-term side effects. In this review, we focused on how deregulation of critical signaling pathways, in particular Notch, PI3K/Akt, MAPK, Jak/STAT and TGF-beta, may contribute to T-ALL. Identifying the alterations that affect intracellular pathways that regulate cell cycle and apoptosis is essential to understanding the biology of this malignancy, to define more effective markers for the correct stratification of patients into appropriate therapeutic regimens and to identify novel targets for the development of specific, less detrimental therapies for T-ALL.
Asunto(s)
Diferenciación Celular , Leucemia-Linfoma de Células T del Adulto , Fosfotransferasas/fisiología , Transducción de Señal/fisiología , Linfocitos T/citología , Humanos , Quinasas Janus/fisiología , Leucemia-Linfoma de Células T del Adulto/etiología , Leucemia-Linfoma de Células T del Adulto/fisiopatología , Leucemia-Linfoma de Células T del Adulto/terapia , Proteínas Quinasas Activadas por Mitógenos/fisiología , Fosfatidilinositol 3-Quinasas/fisiología , Fosforilación , Proteínas Proto-Oncogénicas c-akt/fisiología , Receptores Notch/fisiología , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is a biologically heterogeneous disease with respect to phenotype, gene expression profile and activation of particular intracellular signaling pathways. Despite very significant improvements, current therapeutic regimens still fail to cure a portion of the patients and frequently implicate the use of aggressive protocols with long-term side effects. In this review, we focused on how deregulation of critical signaling pathways, in particular Notch, PI3K/Akt, MAPK, Jak/STAT and TGF-ß, may contribute to T-ALL. Identifying the alterations that affect intracellular pathways that regulate cell cycle and apoptosis is essential to understanding the biology of this malignancy, to define more effective markers for the correct stratification of patients into appropriate therapeutic regimens and to identify novel targets for the development of specific, less detrimental therapies for T-ALL.
Asunto(s)
Humanos , Diferenciación Celular , Leucemia-Linfoma de Células T del Adulto , Fosfotransferasas/fisiología , Transducción de Señal/fisiología , Linfocitos T/citología , /fisiología , Quinasas Janus/fisiología , Leucemia-Linfoma de Células T del Adulto/etiología , Leucemia-Linfoma de Células T del Adulto/fisiopatología , Leucemia-Linfoma de Células T del Adulto/terapia , Proteínas Quinasas Activadas por Mitógenos/fisiología , Fosforilación , Proteínas Proto-Oncogénicas c-akt/fisiología , Receptores Notch/fisiología , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
The authors describe a family (mother, son and two daughters) with mitochondrial myopathy. The mother was asymptomatic. Two daughters had lactic acidosis and myoclonic epilepsy, mild dementia, ataxia, weakness and sensory neuropathy. The son suffered one acute hemiplegic episode due to an ischemic infarct in the right temporal region. All the patients studied had hypertension. EEG disclosed photomyoclonic response in the proband patient. Muscle biopsy disclosed ragged-red fibers and abnormal mitochondria by electron microscopy. Biochemical analysis showed a defect of cytochrome C oxidase in mitochondria isolated from skeletal muscle. Several clinical and genetic aspects of the mitochondrial encephalomyopathies are discussed.
Asunto(s)
Epilepsias Mioclónicas/genética , Mitocondrias Musculares/ultraestructura , Enfermedades Musculares/genética , Acidosis Láctica/complicaciones , Adulto , Electromiografía , Complejo IV de Transporte de Electrones/metabolismo , Epilepsias Mioclónicas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/metabolismo , Músculos/patología , Enfermedades Musculares/sangre , Enfermedades Musculares/complicaciones , Enfermedades Musculares/diagnóstico , LinajeRESUMEN
Kinetic studies of T4 and T3 metabolism were performed on 5 healthy volunteers from Rio de Janeiro to obtain normal values for thyroid hormone metabolism. 125I-T4 and 131I-T3 were administered in bolus and blood samples taken during 7 days. Circulating tracers were isolated by Sephadex G-25 chromatography. The kinetic parameters of T4 and T3 metabolism were calculated by noncompartmental methods. Metabolic clearance rates were 1.04 l/day for T4 and 20.7 l/day for T3. The daily production rate was estimated at 94 micrograms/day for T4 and 23 micrograms/day for T3 and their exchangeable pools at 914 micrograms and 25.5 micrograms, respectively. These values are well within the range of those reported by North American or European authors for normal subjects.