Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Reacción en Cadena en Tiempo Real de la Polimerasa , Quimera por Trasplante , Adulto , Eliminación de Gen , Enfermedad Injerto contra Huésped/diagnóstico , Humanos , Mutación INDEL , Recurrencia Local de Neoplasia/diagnóstico , Polimorfismo Genético , Células Madre/citología , Factores de Tiempo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Healthy radio-exposed individuals who received low levels of Cesium-137 radiation during the accident that occurred in Goiânia in 1987, their families and controls were tested for the detection of t(14;18)-rearranged B cells in peripheral blood by using a highly sensitive, real-time quantitative PCR method. The chromosomal translocation t(14;18)(q32;q21) is characteristic of follicular lymphoma and is a frequent abnormality observed in other types of non-Hodgkin's lymphoma. This translocation leads to constitutive activation of the BCL2 oncogene by the enhancers of the immunoglobulin heavy-chain locus. In healthy individuals, the same translocation may also be found in a small fraction of peripheral blood lymphocytes, and positive cells might serve as an indicator for environmental exposure to carcinogens and possibly correlate with the cumulative risk of developing t(14;18)- positive non-Hodgkin's lymphoma. Twenty healthy radio-exposed individuals, 10 relatives and 10 non-exposed healthy individuals were tested for the detection of this translocation. Only 1 non-exposed individual was positive for the chromosomal translocation, and healthy radio-exposed individuals presented lower levels of cells bearing the BCL2/J(H) rearrangement when compared to the levels of the patients with follicular lymphoma before treatment. However, evaluation of more cells would be required to confirm the total absence of circulating cells bearing BCL2/J(H) rearrangement.
Asunto(s)
Radioisótopos de Cesio/efectos adversos , Genes bcl-2 , Liberación de Radiactividad Peligrosa , Translocación Genética/efectos de la radiación , Adulto , Linfocitos B/efectos de la radiación , Brasil , Línea Celular , Cromosomas Humanos Par 14/efectos de la radiación , Cromosomas Humanos Par 18/efectos de la radiación , Exposición a Riesgos Ambientales/efectos adversos , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma Folicular/etiología , Linfoma Folicular/genética , Linfoma no Hodgkin/etiología , Linfoma no Hodgkin/genética , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/genéticaRESUMEN
The interaction of acute lymphoblastic leukemia (ALL) blasts with bone marrow (BM) stromal cells (BMSCs) has a positive impact on ALL resistance to chemotherapy. We investigated the modulation of a series of putative asparaginase-resistance/sensitivity genes in B-precursor ALL cells upon coculture with BMSCs. Coculture with stromal cells resulted in increased insulin-like growth factor (IGF)-binding protein 7 (IGFBP7) expression by ALL cells. Assays with IGFBP7 knockdown ALL and stromal cell lines, or with addition of recombinant rIGFBP7 (rIGFBP7) to the culture medium, showed that IGFBP7 acts as a positive regulator of ALL and stromal cells growth, and significantly enhances in-vitro resistance of ALL to asparaginase. In these assays, IGFBP7 function occurred mainly in an insulin- and stromal-dependent manner. ALL cells were found to contribute substantially to extracellular IGFBP7 levels in the conditioned coculture medium. Diagnostic BM plasma from children with ALL had higher levels of IGFBP7 than controls. IGFBP7, in an insulin/IGF-dependent manner, enhanced asparagine synthetase expression and asparagine secretion by BMSCs, thus providing a stromal-dependent mechanism by which IGFBP7 protects ALL cells against asparaginase in this coculture system. Importantly, higher IGFBP7 mRNA levels were associated with lower leukemia-free survival (Cox regression model, P=0.003) in precursor B-cell Ph(-) ALL patients (n=147) treated with a contemporary polychemotherapy protocol.
Asunto(s)
Asparaginasa/farmacología , Células de la Médula Ósea/patología , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/fisiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Células del Estroma/patología , Estudios de Casos y Controles , Niño , Preescolar , Técnicas de Cocultivo , Medios de Cultivo Condicionados , Resistencia a Antineoplásicos , Femenino , Citometría de Flujo , Técnicas de Silenciamiento del Gen , Humanos , Lactante , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , ARN Interferente Pequeño , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
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.