Asunto(s)
Haplotipos , Janus Quinasa 2/genética , Mutación , Policitemia Vera/genética , Policitemia Vera/metabolismo , Alelos , Evolución Clonal , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Interferón-alfa/uso terapéutico , Modelos Biológicos , Policitemia Vera/tratamiento farmacológicoRESUMEN
JAK2(V617F) is a gain of function mutation that promotes cytokine-independent growth of myeloid cells and accounts for a majority of myeloproliferative neoplasms (MPN). Mutations in p53 are rarely found in these diseases before acute leukemia transformation, but this does not rule out a role for p53 deregulation in disease progression. Using Ba/F3-EPOR cells and ex vivo cultured CD34(+) cells from MPN patients, we demonstrate that expression of JAK2(V617F) affected the p53 response to DNA damage. We show that E3 ubiquitin ligase MDM2 accumulated in these cells, due to an increased translation of MDM2 mRNA. Accumulation of the La autoantigen, which interacts with MDM2 mRNA and promotes its translation, was responsible for the increase in MDM2 protein level and the subsequent degradation of p53 after DNA damage. Downregulation of La protein or cell treatment with nutlin-3, a MDM2 antagonist, restored the p53 response to DNA damage and the cytokine-dependence of Ba/F3-EPOR-JAK2(V617F) cells. Altogether, these data indicate that the JAK2(V617F) mutation affects p53 response to DNA damage through the upregulation of La antigen and accumulation of MDM2. They also suggest that p53 functional inactivation accounts for the cytokine hypersensitivity of JAK2(V617F) MPN and might have a role in disease progression.
Asunto(s)
Autoantígenos/fisiología , Neoplasias Hematológicas/etiología , Janus Quinasa 2/fisiología , Trastornos Mieloproliferativos/etiología , Proteínas Proto-Oncogénicas c-mdm2/fisiología , Ribonucleoproteínas/fisiología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Autoantígenos/análisis , Línea Celular , Citocinas/fisiología , Daño del ADN , Humanos , Janus Quinasa 2/genética , Ratones , Mutación , Proteínas Proto-Oncogénicas c-mdm2/genética , ARN Mensajero/análisis , Ribonucleoproteínas/análisis , Antígeno SS-BAsunto(s)
Proteínas de Unión al ADN/genética , Células Precursoras Eritroides/enzimología , Interferón-alfa/uso terapéutico , Janus Quinasa 2/genética , Mutación , Polietilenglicoles/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Dioxigenasas , Células Precursoras Eritroides/citología , Humanos , Interferón alfa-2 , Proteínas RecombinantesRESUMEN
The first international meeting on V617F JAK2 mutation in myeloproliferative disorders (MPD) was held by the PV-Nord group on behalf of the French Society of Hematology and Paris 13 University on November 18, 2005, in Paris (France). Twelve speakers, including representatives of the three European groups who discovered the V617F JAK2 mutation and international experts in the field of Philadelphia-negative MPD, presented original biological and clinical data that allow better insight in the relevance of V617F JAK2 mutation in the pathogenesis and management of those diseases. The role of V617F JAK2 in cytokine receptors trafficking and signaling was described. Follow-up of transgenic mice expressing V617F JAK2 showed that they develop typical features of myelofibrosis. Comparisons of JAK2 mutational status to clonality of hematopoiesis in essential thrombocythemia on the one hand, and to activation of transcription factors in myelofibrosis with myeloid metaplasia on the other hand, suggest that JAK2 mutation could be a second genetic event in a subset of patients. Alternatively, other gene mutation(s) have to be found to explain the development of V617F-negative MPD. In large series of MPD patients presented, clinical characteristics of mutated and non-mutated patients were found different. Finally, the place of V617F JAK2 testing in the diagnosis and management of MPD was discussed.
Asunto(s)
Sustitución de Aminoácidos , Janus Quinasa 2/genética , Mutación Missense , Trastornos Mieloproliferativos/genética , Mutación Puntual , Animales , Humanos , Janus Quinasa 2/fisiología , Ratones , Ratones Transgénicos , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/enzimología , Policitemia Vera/genética , Mielofibrosis Primaria/genética , Proteínas Recombinantes de Fusión/fisiología , Trombocitemia Esencial/genéticaRESUMEN
Myeloproliferative disorders (MPDs) are clonal haematopoietic malignancies involving the abnormal proliferation of myeloid lineages. The World Health Organisation (WHO) classification of haematopoietic malignancies distinguishes MPDs from myelodysplastic/ myeloproliferative disorders and systemic mastocytosis. These malignancies frequently involve constitutive tyrosine kinase activity, resulting from either oncogenic fusion protein production or from point mutations. Chronic myelogenous leukaemia is the model used for studies of the consequences of such molecular defects. However, the heterogeneity of the clinical course of MPDs should be seen in a more rationale conceptual framework, including the many molecular events associated with these diseases. This review focuses on the various tyrosine kinase-related molecular mechanisms underlying both MPDs and rare diseases with myeloproliferative features. We pay particular attention to the newly identified JAK2 V617F mutation in polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis and deal with disease heterogeneity and putative additional molecular mechanisms.
Asunto(s)
Genes abl , Trastornos Mieloproliferativos/genética , Proteínas Tirosina Quinasas/genética , Transducción de Señal , Predisposición Genética a la Enfermedad , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Mastocitosis/genética , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/metabolismo , Mutación Puntual , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-kit/genética , Enfermedades Raras/genética , Enfermedades Raras/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Factores de Escisión y Poliadenilación de ARNm/genéticaAsunto(s)
Policitemia Vera/diagnóstico , Policitemia Vera/genética , Policitemia/diagnóstico , Policitemia/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Anciano de 80 o más Años , Autoanálisis , Línea Celular Tumoral , Femenino , Humanos , Janus Quinasa 2 , Masculino , Persona de Mediana Edad , Mutación , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Policitemia Vera/clasificación , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Sensibilidad y Especificidad , TemperaturaRESUMEN
We determined bone marrow karyotype at diagnosis in four female acute myeloid leukemia (AML) or myelodysplasia patients, aged between 52 and 56 years. In each case, we observed chromosome rearrangement involving the same 4q24 band. Three patients had a balanced reciprocal translocation as the sole abnormality - t(3;4)(q26;q24), t(4;5)(q24;p16) and t(4;7)(q24;q21) - and the fourth had del(4)(q23q24), +4. We used a set of 4q BAC probes for fluorescent in situ hybridization (FISH) in these four cases. We found a 4q24 submicroscopic deletion in all three translocations, with a common deletion of approximately 0.5 Mb. In three cases, we concluded that rearrangement occurred in an early hematopoietic stem cell, as it was detected, in mosaic with a normal karyotype, in a fraction of remission bone marrow cells, peripheral T and B lymphocytes, malignant lymph node T-lymphoma cells in one case and B-lymphoblastoid cell lines established in two cases. Moreover, one of 10 additional AML patients tested by FISH had a normal karyotype and deletion of one of the commonly deleted probe sequences. A tumor suppressor gene may therefore be involved, especially as two patients developed malignant lymphoma at the same time as myeloid proliferation.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 4 , Células Madre Hematopoyéticas/patología , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Enfermedad Aguda , Femenino , Reordenamiento Génico , Genes Supresores de Tumor , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide/patología , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Translocación GenéticaRESUMEN
In 1993 a Concerted EU Action was started to coordinate research concerning the immunogenicity of biopharmaceuticals bringing together researchers from academia and industry. The main topic of this concerted action has been interferon alpha. The factors influencing its immunogenicity were studied. Blind panel testing of patients' sera showed large differences in reported titres as an important variable in different studies. The EMEA has requested the three marketing authorization holders of interferon beta to develop a common assay for antibodies to this product. The status of this project will be discussed. The occurrence of about 30 cases of pure red cell aplasia related to antibodies induced by erythropoietin treatment will also be reported.
Asunto(s)
Factores Biológicos/inmunología , Biofarmacia , Eritropoyetina/inmunología , Unión Europea , Humanos , Interferón beta/inmunología , Mercadotecnía , Proteínas Recombinantes , Aplasia Pura de Células Rojas/etiología , Aplasia Pura de Células Rojas/inmunologíaRESUMEN
BACKGROUND: Non-cirrhotic portal hypertension of unknown cause is a poorly understood condition attributed to obstructive portal venopathy. AIM: To reassess the manifestations, course, and causes, with special attention to thrombosis. METHODS: Analysis of a cohort of 28 patients. RESULTS: Gastrointestinal bleeding occurred in 11 patients. Liver failure developed at the time of concurrent disease in eight patients, including all four patients who died. Portal vein thrombosis developed in 13 patients. A prothrombotic disorder was found in 12 of 23 fully investigated patients. Hepatoportal sclerosis was observed in 11 patients (with associated perisinusoidal fibrosis and/or nodular regenerative hyperplasia in six); periportal fibrosis, perisinusoidal fibrosis, nodular regenerative hyperplasia, or a combination thereof were observed in other patients. A morphometric evaluation showed an increased number of portal vessels in patients with hepatoportal sclerosis. There was no relation between pathological results and haemodynamic findings or prothrombotic disorders. CONCLUSIONS: Outcome was related to associated conditions. Overlap in pathological, haemodynamic, and causal features suggests a single entity, with prothrombotic disorders as major causal factors, and injury to sinusoids as well as to portal venules as the primary mechanism. Activated coagulation could mediate vascular injury in the absence of thrombosis. Anticoagulation should be considered.
Asunto(s)
Hipertensión Portal/patología , Hígado/patología , Adulto , Femenino , Estudios de Seguimiento , Hemorragia Gastrointestinal/etiología , Humanos , Hipertensión Portal/diagnóstico por imagen , Hígado/diagnóstico por imagen , Cirrosis Hepática , Masculino , Vena Porta , Radiografía , Esclerosis , Trombosis/patología , UltrasonografíaRESUMEN
In a 70 year old man with primary glomerulonephritis, severe anemia occurred after 4 years on hemodialysis and rHu-EPO. The usual mechanisms of EPO-resistance were excluded. A bone marrow sample showed red all aplasia. No circulating EPO could be detected; the serum inhibited the growth of erythroid precursors in bone marrow cultures. Immunoprecipitation identified an IgG anti-EPO, still active against deglycosylated EPO, i.e. directed against the peptidic matrix. Its high neutralising capacity and the absence of any immune abnormality rule out an auto-antibody. Anti-rHu EPO immunisation is a very rare occurrence, made severe by transfusion-dependence and the risk of hemosiderosis. An immuno-modulating treatment can therefore be justified.
Asunto(s)
Anemia/tratamiento farmacológico , Eritropoyetina/inmunología , Inmunoglobulina G/inmunología , Isoanticuerpos/inmunología , Anciano , Anemia/sangre , Anemia/etiología , Angiodisplasia/complicaciones , Transfusión Sanguínea , Médula Ósea/patología , División Celular/efectos de los fármacos , Terapia Combinada , Sistema Digestivo/irrigación sanguínea , Resistencia a Medicamentos/inmunología , Células Precursoras Eritroides/patología , Eritropoyetina/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Hematemesis/tratamiento farmacológico , Hematemesis/etiología , Hematemesis/terapia , Humanos , Inmunoglobulina G/biosíntesis , Isoanticuerpos/biosíntesis , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Leucemia Eritroblástica Aguda/patología , Masculino , Melena/tratamiento farmacológico , Melena/etiología , Melena/terapia , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéutico , Diálisis Renal , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Immune-mediated disorders of erythropoiesis can result in acquired severe anemia, low reticulocyte counts, and bone marrow exhibiting pure red cell aplasia or ineffective erythropoiesis. Erythropoiesis can be suppressed or impaired by humoral or cellular mechanisms. In vitro inhibition of erythroid colony growth by immunoglobulins or lymphocytes can be a strong argument for the immune origin of the disease. Classical etiologies are thymoma and hematologic malignancies such as chronic lymphocytic leukemia (CLL). Clonal proliferation of T cells has been incriminated. Recently, acquired circulating autoantibodies directed against erythropoietin have been detected in a case of pure red cell aplasia. Autoimmune mechanisms have also been detected or suggested in synartesis and in Fas-associated dyserythropoiesis, two distinct syndromes recently described where morphologic abnormalities specific to the erythroid lineage illustrate ineffective erythropoiesis.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Eritropoyesis/inmunología , Animales , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/etiología , Humanos , Aplasia Pura de Células Rojas/complicaciones , Aplasia Pura de Células Rojas/inmunología , Receptor fas/metabolismoRESUMEN
BACKGROUND: The role of factor V Leiden as a cause of Budd-Chiari syndrome has only recently been described. AIMS: To assess the specific features of factor V Leiden related Budd-Chiari syndrome. PATIENTS: Sixty three consecutive patients with hepatic vein or terminal inferior vena cava thrombosis. METHODS: Standardised chart review. RESULTS: Factor V Leiden was found in 20 patients (31% (95% CI 20-43)). In the subgroup of patients with, compared with the subgroup without, factor V Leiden, a combination of prothrombotic states was more common (70% (95% CI 50-90) v 14% (95% CI 3-24)); inferior vena cava thrombosis was more frequent (40% (95% CI 19-61) v 7% (95% CI 0-14)); and distribution of initial alanine aminotransferase values was bimodal (almost normal or extremely increased) versus unimodal (p=0.003). Factor V Leiden accounted for four of five cases of massive ischaemic necrosis (transaminases >50-fold the upper limit of normal values) (p=0.014), and also for all three cases developing during pregnancy. Patients with and without factor V Leiden did not differ with regard to mortality, portosytemic shunting, or listing for liver transplantation. Hepatocellular carcinoma developed in two patients; both had factor V Leiden and indolent obstruction of the inferior vena cava. CONCLUSIONS: In patients with Budd-Chiari syndrome, factor V Leiden (a) is common; (b) precipitates thrombosis mostly when combined with another risk factor; (c) is associated with one of two contrasting clinical pictures: indolent thrombosis-particularly of the inferior vena cava-or massive ischaemic necrosis; and (d) is a major cofactor of Budd-Chiari syndrome developing during pregnancy.
Asunto(s)
Síndrome de Budd-Chiari/genética , Factor V/genética , Trombofilia/genética , Adulto , Alanina Transaminasa/sangre , Síndrome de Budd-Chiari/diagnóstico , Síndrome de Budd-Chiari/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Embarazo , Complicaciones Hematológicas del Embarazo/etiología , Proteína C/metabolismo , Factores de Riesgo , Trombofilia/diagnóstico , Trombofilia/metabolismoRESUMEN
Immune-mediated acquired disorders of erythropoiesis can result in pure red cell aplasia or ineffective erythropoiesis. Erythropoiesis can be suppressed or impaired by humoral or cellular mechanisms. In vitro inhibition of erythroid colony growth by humoral factors or lymphocytes is a strong argument for the immune origin of the disease. Classical aetiologies are thymoma and hematological malignancies such as chronic lymphocytic leukaemia. Clonal proliferation of T cells has also been incriminated. Recently, acquired circulating autoantibodies directed against erythropoietin have been detected in a case of pure red cell aplasia. Autoimmune mechanisms have also been suggested in two dyserythropoietic syndromes recently described.
Asunto(s)
Anemia/inmunología , Enfermedades Autoinmunes/inmunología , Eritropoyesis/inmunología , Aplasia Pura de Células Rojas/inmunología , Anemia/fisiopatología , Enfermedades Autoinmunes/patología , División Celular , Eritropoyetina/inmunología , Humanos , Leucemia Linfocítica Crónica de Células B/fisiopatología , Aplasia Pura de Células Rojas/fisiopatología , Linfocitos T/inmunología , Timoma/fisiopatologíaRESUMEN
We describe two patients with positive t(15;17) acute promyelocytic leukaemia (APL) that developed into a therapy-related myelodysplasia 2-2.5 years after complete remission (CR) and then evolved into therapy-related acute myeloid leukaemia (t-AML). Both patients received anthracyclines as potential leukaemogenic drugs. In both cases, cytogenetic changes usually occurring after use of alkylating agents were noticed: monosomy 7 associated with monosomy 5 or 5q- chromosome. A review of the literature on t-AML occurring after successful therapy for APL showed only one report similar to these two cases. These observations suggest that anthracyclines can cause t-AML similar to that induced by alkylating agents.
Asunto(s)
Antibióticos Antineoplásicos/efectos adversos , Leucemia Mieloide/inducido químicamente , Leucemia Promielocítica Aguda/tratamiento farmacológico , Adulto , Antibióticos Antineoplásicos/uso terapéutico , Niño , Cromosomas Humanos Par 15 , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 5 , Cromosomas Humanos Par 7 , Femenino , Humanos , Cariotipificación , Leucemia Mieloide/complicaciones , Leucemia Mieloide/genética , Leucemia Promielocítica Aguda/complicaciones , Leucemia Promielocítica Aguda/genética , Masculino , Persona de Mediana Edad , Monosomía , Recurrencia , Translocación GenéticaAsunto(s)
Eritropoyetina/uso terapéutico , Anemia/tratamiento farmacológico , Anemia/etiología , Antineoplásicos/efectos adversos , Transfusión de Sangre Autóloga , Eritropoyetina/administración & dosificación , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Neoplasias/sangre , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Diálisis Renal/efectos adversosRESUMEN
In acute myeloid leukemia (AML) patients, a variety of clinical and biologic parameters, including phenotype, have been examined for potential value in predicting treatment response and survival. The European Group for the Immunological Classification of Leukaemias (EGIL) has proposed that AML be defined immunologically by the expression of 2 or more of the following myeloid markers: myeloperoxidase, CD13, CD33, CDw65, and CD117. With regard to this classification, the prognostic significance of 21 antigens taken separately and with immunophenotypic subgroups were evaluated and compared with other clinical and biological variables in 177 adult AML patients. None of the antigens tested were associated with treatment outcome. In contrast, patients with blasts disclosing a full expression of panmyeloid phenotype (defined by the expression of all 5 myeloid markers) had a higher complete remission rate (P <. 0001) and differed significantly in disease-free survival (P =.02) and overall survival (P =.008) than patients whose cells expressed fewer than 5 of these markers. In multivariate analysis, only age, panmyeloid phenotype, performance status, and permeability glycoprotein activity influence treatment outcome. Cytogenetics was significant in univariate analysis but not in multivariate analysis, most likely because of the redundancy with panmyeloid phenotype and a higher sensitivity of immunophenotyping. Patients whose cells exhibit the panmyeloid phenotype appear to define a relatively homogeneous biological subset of AML. The 4 independent prognostic factors were used to create a prognostic score, defined by the number of factors present. This score permitted a stratification of patients with AML, thereby allowing for the consideration of innovative therapies to improve outcome in the poorer outcome groups.
Asunto(s)
Antígenos CD , Inmunofenotipificación , Leucemia Mieloide/inmunología , Leucemia Mieloide/fisiopatología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores , Femenino , Humanos , Leucemia Mieloide/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del TratamientoRESUMEN
Repeated cycles of intravenous immunoglobulins (IVIG) have been reported to be successful in a few patients with idiopathic pure red cell aplasia (PRCA) or associated with another pathology. The efficacy of this treatment for PRCA with thymoma has not been reported previously. We describe here the case of a 75-yr-old man who presented with PRCA associated with a benign thymoma. After failure of thymectomy, corticosteroids and octreotide, a complete durable remission was obtained after a single 5-d cycle of IVIG.
Asunto(s)
Enfermedades Autoinmunes/terapia , Inmunoglobulinas Intravenosas/uso terapéutico , Aplasia Pura de Células Rojas/terapia , Timoma/complicaciones , Neoplasias del Timo/complicaciones , Corticoesteroides/uso terapéutico , Anciano , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/etiología , Terapia Combinada , Humanos , Inmunosupresores/uso terapéutico , Masculino , Octreótido/uso terapéutico , Aplasia Pura de Células Rojas/tratamiento farmacológico , Aplasia Pura de Células Rojas/etiología , Inducción de Remisión , Timectomía , Timoma/cirugía , Neoplasias del Timo/cirugíaRESUMEN
According to a recent hypothesis, venous thrombosis results from the concurrence of several factors. This hypothesis was assessed in patients with portal or hepatic venous thrombosis by simultaneously investigating most of the currently identified prothrombotic disorders, local precipitating factors, and other risk factors such as oral contraceptive use. Patients with a tumorous obstruction and patients with cirrhosis with portal vein thrombosis were excluded. The prothrombotic disorders that were investigated included classical and occult myeloproliferative disorders; antiphospholipid syndrome; protein C; protein S and antithrombin deficiency; factor V Leiden; factor II; and methylene-tetrahydrofolate-reductase gene mutations. We found 1 or several prothrombotic disorders and a local precipitating factor in 26 and 10 of the 36 patients with portal vein thrombosis, respectively; and in 28 and none of the 32 patients with hepatic vein thrombosis, respectively. We found a combination of prothrombotic disorders in 5 and 9 patients with portal and hepatic vein thrombosis, respectively, whereas such a combination is expected in less than 1% of asymptomatic subjects. Of the 10 patients with a local precipitating factor, 8 had a prothrombotic disorder. Of the 13 patients who use oral contraceptives, 10 had a prothrombotic disorder. We conclude that portal or hepatic venous thrombosis should be regarded as an index for 1 or several prothrombotic disorders, whether or not local precipitating factors or oral contraceptive use are found. Concurrence of prothrombotic disorders is more common than expected. Extensive investigation of prothrombotic disorders and anticoagulation should be considered in patients with portal or hepatic venous thrombosis.