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1.
Oncogene ; 21(29): 4473-80, 2002 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-12085225

RESUMO

The Epstein-Barr virus (EBV) transforms B cells in part by inhibiting the cellular apoptotic programme. This is also observed when Burkitt lymphoma cell lines are infected with EBV. Induction of apoptosis is one of the mechanisms by which fludarabine inhibits the growth of cells with low proliferative capacity. This compound can also inhibit several other mechanisms in the cell, including inhibition of the synthesis of factors such as STAT1. To analyse the relationship between EBV status, fludarabine-induced apoptosis, and transcription factors we studied the EBV-negative Burkitt lymphoma cell line BL2, its EBV-infected counterpart BL2.B95.8 and the EBV-transformed cell line PRI. The BL2 cell line was found to be very sensitive to fludarabine. The BL2.B95.8 and PRI cells were both resistant but the latter to a lesser extent. In the PRI cells fludarabine activated p53, but not in the BL2.B95.8 cells in which the p53 pathway is inactivated. We observed that this inactivation results in part from the lack of expression of the MDM2 inhibitor p14ARF. Conversely, there was a substantial constitutive activation of STAT1, and not of the other STATs, in the BL2.B95.8 cells and a modest one in the PRI cells. Furthermore, expression of STAT1 was significantly reduced by fludarabine treatment in the PRI cells, but not in the BL2.BL95.8 cells. Finally, the expression of p21WAF1/CIP1 was detected only in the BL2.B95.8 and PRI cells. This protein, known to play a role in cell survival, may therefore be involved in the resistance of the BL2.B95.8 cells to fludarabine.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/virologia , Resistencia a Medicamentos Antineoplásicos , Herpesvirus Humano 4/fisiologia , Vidarabina/farmacologia , Linfócitos B/patologia , Western Blotting , Linhagem Celular , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Reação em Cadeia da Polimerase , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT1 , Transativadores/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Vidarabina/análogos & derivados
2.
Blood ; 100(7): 2349-56, 2002 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-12239142

RESUMO

Myelodysplastic syndromes (MDSs) are heterogeneous diseases of bone marrow (BM) cell precursors for which immunophenotypic characterization is still considered irrelevant despite the accuracy and sensitivity of flow cytometry techniques. The aim of this study was to determine whether immunophenotypic abnormalities could be defined in MDSs and could correlate with the French-American-British classification and cytogenetics. Analysis was performed on 275 BM samples (207 MDS patients, 68 controls) and 25 control blood samples. Immunophenotyping was based on a primary gating of blast cells, monocytes, and granulocytes according to CD45 antigen expression and side scatter light diffraction. Immunophenotypic hierarchical clustering was performed to analyze the results. The data obtained show that (1) immunophenotypic clustering partly discriminates patients with refractory anemia with excess blasts/refractory anemia with excess blasts in transformation (RAEB/RAEB-T), chronic myelomonocytic leukemia (CMML), and refractory anemia/refractory anemia with ring sideroblasts (RA/RARS) for CD45(lo) blast cells and patients with RA/CMML, RARS, and RAEB/RAEB-T for CD45(hi)/side scatter(hi) (SS(hi)) granulocytes; (2) the most discriminating markers were CD16, CD34, CD36, CD38, CD71, and HLA-DR for blast cells and CD11b, CD13, CD33, CD36, CD38, CD71, and HLA-DR for CD45(hi)/SS(hi) granulocytes; (3) clusters related to CD34 expression were associated with high levels of blast cells on BM smear; (4) clusters related to high levels of CD36 expression on CD45(lo) blast cells and CD45(hi)/SS(hi) granulocytes were associated with a poor International Prognosis Scoring System score; and (5) high levels of CD71 expression on CD45(hi)/SS(hi) granulocytes were associated with the RARS category. These results show a close relationship between immunophenotypic abnormalities and BM dysplasia and suggest that flow cytometry could be a future tool for the characterization of MDSs.


Assuntos
Antígenos CD/análise , Imunofenotipagem/classificação , Síndromes Mielodisplásicas/imunologia , Antígenos CD/imunologia , Antígenos CD34/análise , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Análise por Conglomerados , Humanos , Imunofenotipagem/métodos , Antígenos Comuns de Leucócito/análise , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/patologia
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