Assuntos
Transplante de Células-Tronco Hematopoéticas , Reação em Cadeia da Polimerase em Tempo Real , Quimeras de Transplante , Adulto , Deleção de Genes , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Mutação INDEL , Recidiva Local de Neoplasia/diagnóstico , Polimorfismo Genético , Células-Tronco/citologia , Fatores de Tempo , Transplante Homólogo , Resultado do TratamentoRESUMO
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.
Assuntos
Radioisótopos de Césio/efeitos adversos , Genes bcl-2 , Liberação Nociva de Radioativos , Translocação Genética/efeitos da radiação , Adulto , Linfócitos B/efeitos da radiação , Brasil , Linhagem Celular , Cromossomos Humanos Par 14/efeitos da radiação , Cromossomos Humanos Par 18/efeitos da radiação , Exposição Ambiental/efeitos adversos , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma Folicular/etiologia , Linfoma Folicular/genética , Linfoma não Hodgkin/etiologia , Linfoma não Hodgkin/genética , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/genéticaRESUMO
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.