RESUMEN
The aberrant expression of tissue factor (TF) in acute promyelocytic leukemia (APL) cells has been implicated in the pathogenesis of the APL coagulopathy. In this study, we found that in APL patients receiving ATRA or As2O3 treatment, the improvement in hypercoagulobility and hyperfibrinolysis paralleled the correction of plasma fibrinogen level and amelioration of bleeding symptoms. Notably, clinical improvement was also correlated to ATRA/As2O3-induced rapid decrease of membrane procoagulant activity (PCA) and TF contents of APL blasts. Consistent with the in vivo findings, the membrane PCA, TF antigen and its mRNA level within NB4 cells were rapidly down-regulated by 1 microM ATRA or As2O3, while 0.2 microg/ml DNR increased these TF parameters prior to its effect upon apoptosis induction. The down-regulation of TF mRNA by ATRA was partially de novo protein synthesis-dependent and at least partially attributed to a mechanism of destabilizing TF mRNA. On the other hand, in addition to its modulation on mRNA, As2O3 could also induce an accelerated TF protein turnover. These distinct effects were corroborated with the properties of these agents in causing the degradation of PML-RARalpha protein. All three therapeutic agents, however, enhanced the potential of NB4 cells to stimulate the expression of TF and PCA in endothelium. Taken together, our data suggest that the rapid and distinct regulation of TF on APL cells by these therapeutic agents might at least partially contribute to their effects on APL coagulopathy.
Asunto(s)
Antineoplásicos/uso terapéutico , Arsenicales/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Óxidos/uso terapéutico , Tromboplastina/biosíntesis , Tretinoina/uso terapéutico , Adolescente , Adulto , Trióxido de Arsénico , Coagulación Sanguínea/efectos de los fármacos , Daunorrubicina/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Femenino , Fibrinólisis/efectos de los fármacos , Humanos , Leucemia Promielocítica Aguda/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RARalpha and one of four fusion partners: PML, PLZF, NPM, and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo, we generated transgenic mice with PLZF-RARalpha and NPM-RARalpha. PLZF-RARalpha transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage of life (within 3 months in five of six mice), whereas three NPM-RARalpha transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZF-RARalpha transgenic mice, those from NPM-RARalpha transgenic mice could be induced to differentiate by all-trans-retinoic acid (ATRA). We also studied RARE binding properties and interactions between nuclear corepressor SMRT and various fusion proteins in response to ATRA. Dissociation of SMRT from different receptors was observed at ATRA concentrations of 0.01 microM, 0.1 microM, and 1.0 microM for RARalpha-RXRalpha, NPM-RARalpha, and PML-RARalpha, respectively, but not observed for PLZF-RARalpha even in the presence of 10 microM ATRA. We also determined the expression of the tissue factor gene in transgenic mice, which was detected only in bone marrow cells of mice expressing the fusion genes. These data clearly establish the leukemogenic role of PLZF-RARalpha and NPM-RARalpha and the importance of fusion receptor/corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.
Asunto(s)
Proteínas de Unión al ADN/genética , Leucemia Promielocítica Aguda/genética , Proteínas de Fusión Oncogénica/genética , Receptores de Ácido Retinoico/genética , Factores de Transcripción/genética , Animales , Antígenos Nucleares , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/patología , Proteínas de Ciclo Celular , Diferenciación Celular/efectos de los fármacos , Gonadotropina Coriónica/genética , Crecimiento , Humanos , Factores de Transcripción de Tipo Kruppel , Leucemia Promielocítica Aguda/patología , Leucemia Promielocítica Aguda/fisiopatología , Ratones , Ratones Transgénicos , Proteínas Asociadas a Matriz Nuclear , Proteínas Nucleares/genética , Fenotipo , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Receptor alfa de Ácido Retinoico , Translocación Genética , Tretinoina/farmacología , Dedos de ZincRESUMEN
This paper reports 14 dermatoglyphic parameters of 1000 Tibetans sampled in Tibet. Relatedness between Tibetans and Hans is much closer than that between Tibetans and Minnesotians in the USA. Compared with 12 nationalities. The Tibetan showed smaller difference with the Hani and the Han and greater difference with the Uygur. Comparison among the Tibetans living in different regions suggests that the Tibetans in Tibet have less difference with the Tibetans in Pingwu Region of Sichuan Province and much difference with the Tibetans in Gannan Region of Gansu Province. This report indicates that dermatoglyphic Parameters should not be used indifferently in different ethnic groups or even in different geographic groups of the same nationality.