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1.
Bone Marrow Transplant ; 50(4): 585-91, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25621801

RESUMEN

Allogeneic hematopoietic SCT (allo-SCT) is a promising therapy that may provide long-term durable remission for adult T-cell leukemia-lymphoma (ATL) patients; however, the incidence of relapse associated with ATL remains high. To determine the clinical features of these patients at relapse, we retrospectively analyzed tumor lesions in 30 or 49 patients who relapsed following allo-SCT or chemotherapy (CHT), respectively, at three institutions in Nagasaki prefecture between 1997 and 2011. A multivariate analysis revealed that the development of abnormal lymphocytes in the peripheral blood of patients at relapse was less frequent after allo-SCT than after CHT (P<0.001). Furthermore, relapse with a new lesion only in the absence of the primary lesion was more frequent in allo-SCT (P=0.014). Lesions were more frequently observed in the central nervous systems of patients who relapsed with new lesions only (P=0.005). Thus, the clinical manifestation of relapsed ATL was slightly complex, especially in post-transplant patients. Our results emphasized the need to develop adoptive modalities for early and accurate diagnoses of relapsed ATL.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma de Células T del Adulto , Adulto , Anciano , Anciano de 80 o más Años , Aloinjertos , Femenino , Humanos , Japón , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/patología , Leucemia-Linfoma de Células T del Adulto/terapia , Linfocitos/patología , Masculino , Persona de Mediana Edad , Recurrencia
2.
Leukemia ; 28(7): 1459-66, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24457336

RESUMEN

Myeloperoxidase (MPO) has been associated with both a myeloid lineage commitment and favorable prognosis in patients with acute myeloid leukemia (AML). DNA methyltransferase inhibitors (decitabine and zeburaline) induced MPO gene promoter demethylation and MPO gene transcription in AML cells with low MPO activity. Therefore, MPO gene transcription was directly and indirectly regulated by DNA methylation. A DNA methylation microarray subsequently revealed a distinct methylation pattern in 33 genes, including DNA methyltransferase 3 beta (DNMT3B), in CD34-positive cells obtained from AML patients with a high percentage of MPO-positive blasts. Based on the inverse relationship between the methylation status of DNMT3B and MPO, we found an inverse relationship between DNMT3B and MPO transcription levels in CD34-positive AML cells (P=0.0283). In addition, a distinct methylation pattern was observed in five genes related to myeloid differentiation or therapeutic sensitivity in CD34-positive cells from AML patients with a high percentage of MPO-positive blasts. Taken together, the results of the present study indicate that MPO may serve as an informative marker for identifying a distinct and crucial DNA methylation profile in CD34-positive AML cells.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Peroxidasa/genética , Antígenos CD34/metabolismo , Médula Ósea/patología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Proteínas Potenciadoras de Unión a CCAAT/genética , Línea Celular Tumoral , Análisis por Conglomerados , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Epigénesis Genética , Perfilación de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Mutación , Proteínas Nucleares/genética , Nucleofosmina , Peroxidasa/metabolismo , Tirosina Quinasa 3 Similar a fms/genética , ADN Metiltransferasa 3B
3.
Leukemia ; 22(5): 956-64, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18273043

RESUMEN

Myeloperoxidase (MPO), a pivotal lineage marker for acute myeloid leukemia (AML), has been also shown to have a prognostic value: a high percentage of MPO-positive blasts correlates to favorable prognosis. To understand the relationship between the expression of MPO in leukemia cells and the response to chemotherapeutic agents, we established MPO-expressing K562 leukemia cell lines and then treated them with cytosine arabinocide (AraC). Cells expressing wild-type MPO, but not mutant MPO that could not mature, died earlier of apoptosis than control K562 cells. Reactive oxygen species (ROS) were generated more in leukemia cells expressing MPO, and the generation was abrogated by MPO inhibitors or antioxidants. Tyrosine nitration of cellular protein also increased more in MPO-expressing K562 cells than control cells after treatment with AraC. In clinical samples, CD34-positive AML cells from high-MPO cases showed a tendency to be sensitive to AraC in the colony-formation assay, and the generation of ROS and the nitration of protein were observed only when the percentage of MPO-expressing cells was high. These data suggest that MPO enhances the chemosensitivity of AML through the generation of ROS and the nitration of proteins.


Asunto(s)
Antineoplásicos/farmacología , Leucemia/patología , Peroxidasa/fisiología , Procesamiento Proteico-Postraduccional , Especies Reactivas de Oxígeno/metabolismo , Humanos , Células K562 , Leucemia/metabolismo , Nitrosación , Peroxidasa/análisis , Células Tumorales Cultivadas
4.
Haematologica ; 93(1): e21-3, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18166773

RESUMEN

Primary effusion lymphoma (PEL) was initially designated as a body-cavity-based lymphoma and recognized as a distinct clinical entity without a contiguous tumor mass. PEL was first reported in patients with acquired immunodeficiency syndrome (AIDS) and the distinctive feature of PEL originally reported as a B-cell neoplasm characterized by infection of the tumor cells by human herpes virus 8 (HHV-8). However, there have recently been several reports of PEL in patients without human immunodeficiency virus (HIV) or HHV-8 infection.


Asunto(s)
Antígenos CD4/biosíntesis , Proteínas de Unión al ADN/genética , Reordenamiento Génico , Herpesvirus Humano 8/genética , Linfoma de Efusión Primaria/genética , Linfopenia/terapia , Linfocitos T/metabolismo , Anciano , Antineoplásicos/farmacología , Disnea/diagnóstico , Infecciones por VIH/diagnóstico , Herpesvirus Humano 8/metabolismo , Humanos , Inmunofenotipificación , Linfoma de Efusión Primaria/complicaciones , Linfoma de Efusión Primaria/terapia , Linfopenia/complicaciones , Masculino , Derrame Pericárdico , Proteínas Proto-Oncogénicas c-bcl-6
5.
Leukemia ; 21(6): 1212-7, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17410191

RESUMEN

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can provide long-term remission for patients with adult T-cell leukemia/lymphoma (ATLL) caused by human retrovirus, human T-lymphocyte virus (HTLV-1). To understand how HTLV-1-positive cells including ATLL cells were suppressed by allo-HSCT, we examined HTLV-1 provirus load and residual ATLL cells in peripheral blood of transplant recipients using PCR-based tests. We found that the copy number of HTLV-1 genome, called provirus, became very small in number after allo-HSCT; however, in most cases, provirus did not disappear even among long-term survivors. Tumor-specific PCR tests demonstrated that most of HTLV-1-positive cells that remained long after transplantation were not primary ATLL cells but donor-derived HTLV-1-positive cells. We also found a case having very low amount of residual disease in peripheral blood even long after transplantation. There was only one recipient in whom we failed to show the presence of HTLV-1 genome and antibody against HTLV-1 even with an extensive search, which strongly suggested the elimination of HTLV-1 after allo-HSCT. These results demonstrated that after allo-HSCT the small amount of residual HTLV-1-positive cells were heterogeneous in origin and that long-term disease control for ATLL could be obtained without the complete elimination of HTLV-1.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Leucemia-Linfoma de Células T del Adulto/terapia , Adulto , Humanos , Leucemia-Linfoma de Células T del Adulto/patología , Reacción en Cadena de la Polimerasa , Inducción de Remisión , Donantes de Tejidos , Trasplante Homólogo , Carga Viral
6.
J Immunol ; 165(7): 3907-16, 2000 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-11034398

RESUMEN

The present study investigates the regulatory mechanisms involved in the cooperation between IFN-gamma and TNF-alpha to promote transcription from IFN regulatory factor-1 (IRF-1). A transient transfection analysis revealed that the region between -218 and -144, where +1 is the transcription start site, as well as previously reported downstream elements, ppkappaB and IFN-gamma activation site/kappaB, were required for the optimal response to the two cytokines. A subsequent DNase I footprint analysis showed that the region between -171 and -144 was inducibly protected with stimulation by TNF-alpha, and this protection was significantly enhanced with the combination of IFN-gamma and TNF-alpha. In an EMSA with the protected region as a probe, a TNF-alpha-inducible complex (C1) and an IFN-gamma-inducible complex (C2), but no synergy-specific DNA-protein complexes, were recognized. The C1 complex consisted of a pre-existing factor (p65/p50), whereas the C2 complex consisted of a newly synthesized IRF-1-related factor. A methylation interference assay revealed the critical G residues (from -167 to -151) for the DNA-protein complex formation specific to the cytokine response, and within this region the novel kappaB sequence, the promoter distal kappaB (pdkappaB) element (5'-GGGGAAG TAC-3'), was identified. Because the base substitutions over the pdkappaB region (from -171 to -144) affected not only the TNF-alpha-response but also that of IFN-gamma, this region might contribute to the cooperative action of the NF-kappaB subunits with the IRF-1-related factor. Finally, we demonstrated that none of the cis-acting elements, ppkappaB, pdkappaB, or IFN-gamma activation site/kappaB, is dispensable for the optimal synergism in response to IFN-gamma and TNF-alpha.


Asunto(s)
Citocinas/fisiología , Proteínas de Unión al ADN/genética , Fosfoproteínas/genética , Regiones Promotoras Genéticas/inmunología , Elementos de Respuesta/inmunología , Adyuvantes Inmunológicos/fisiología , Sitios de Unión/genética , Sitios de Unión/inmunología , Células Cultivadas , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/aislamiento & purificación , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/inmunología , Humanos , Factor 1 Regulador del Interferón , Interferón gamma/metabolismo , Interferón gamma/fisiología , Células K562 , FN-kappa B/biosíntesis , FN-kappa B/aislamiento & purificación , FN-kappa B/metabolismo , Subunidad p50 de NF-kappa B , Fosfoproteínas/análisis , Factor de Transcripción ReIA , Factores de Transcripción/biosíntesis , Factores de Transcripción/metabolismo , Transcripción Genética/inmunología , Factor de Necrosis Tumoral alfa/fisiología , Células U937
7.
Exp Hematol ; 27(3): 433-40, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10089905

RESUMEN

We investigated the expression of Fas antigen (CD95) in the pure erythroid cell line AS-E2 in the presence and absence of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). TNF-alpha induced apoptosis in AS-E2 cells, whereas IFN-gamma did not. In culture containing no IFN-gamma or TNF-alpha, AS-E2 cells expressed little Fas antigen. However, IFN-gamma and IFN-gamma and TNF-alpha both induced expression of Fas antigen and its mRNA within 24 hours after the stimulation. When anti-Fas monoclonal antibody (IgM) was added to AS-E2 cells after the induction of Fas expression, AS-E2 cells underwent apoptosis as shown by the induction of DNA fragmentation. This apoptotic change was inhibited by an inhibitor of caspase-3-like proteases (Ac-DEVD-CHO) and an inhibitor of CED-3/ICE family proteases (Z-Asp-CH2-DCB) but not by an inhibitor of caspase-1-like proteases (Ac-YVAD-CHO), suggesting a role for caspase-3-like proteases in Fas-receptor signaling. Although AS-E2 cells expressed Fas ligand mRNA, treatment with ZB4, an antibody that inhibits Fas-mediated cell death, failed to suppress IFN-gamma- or TNF-alpha-mediated cytotoxicity. These findings suggest that the late erythroid progenitor cells are negatively regulated by IFN-gamma and TNF-alpha, both of which are capable of inducing functional Fas expression.


Asunto(s)
Apoptosis/efectos de los fármacos , Células Precursoras Eritroides/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Interferón gamma/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Receptor fas/biosíntesis , Anticuerpos Monoclonales/farmacología , Apoptosis/fisiología , Ácido Aspártico/análogos & derivados , Ácido Aspártico/farmacología , Caspasa 3 , Inhibidores de Caspasas , Caspasas/biosíntesis , Caspasas/fisiología , División Celular/efectos de los fármacos , Fragmentación del ADN , Inhibidores Enzimáticos/farmacología , Células Precursoras Eritroides/citología , Células Precursoras Eritroides/metabolismo , Proteína Ligando Fas , Humanos , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/genética , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Oligopéptidos/farmacología , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , Proteínas Recombinantes , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Receptor fas/genética , Receptor fas/fisiología
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