RESUMEN
The hypoxia-inducible factors (HIFs; isoforms HIF-1α, HIF-2α, HIF-3α) mediate many responses to hypoxia. Their regulation is principally by oxygen-dependent degradation, which is initiated by hydroxylation of specific proline residues followed by binding of von Hippel-Lindau (VHL) protein. Chuvash polycythemia is a disorder with elevated HIF. It arises through germline homozygosity for hypomorphic VHL alleles and has a phenotype of hematological, cardiopulmonary, and metabolic abnormalities. This study explores the phenotype of two other HIF pathway diseases: classic VHL disease and HIF-2α gain-of-function mutation. No cardiopulmonary abnormalities were detected in classic VHL disease. HIF-2α gain-of-function mutations were associated with pulmonary hypertension, increased cardiac output, increased heart rate, and increased pulmonary ventilation relative to metabolism. Comparison of the HIF-2α gain-of-function responses with data from studies of Chuvash polycythemia suggested that other aspects of the Chuvash phenotype were diminished or absent. In classic VHL disease, patients are germline heterozygous for mutations in VHL, and the present results suggest that a single wild-type allele for VHL is sufficient to maintain normal cardiopulmonary function. The HIF-2α gain-of-function phenotype may be more limited than the Chuvash phenotype either because HIF-1α is not elevated in the former condition, or because other HIF-independent functions of VHL are perturbed in Chuvash polycythemia.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Dióxido de Carbono/sangre , Fenómenos Fisiológicos Cardiovasculares/genética , Regulación de la Expresión Génica/fisiología , Oxígeno/sangre , Enfermedad de von Hippel-Lindau/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/sangre , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Estudios de Casos y Controles , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Mutación , Enfermedad de von Hippel-Lindau/sangre , Enfermedad de von Hippel-Lindau/genéticaRESUMEN
Hypoxia-inducible factor (HIF) alpha, which has three isoforms, is central to the continuous balancing of the supply and demand of oxygen throughout the body. HIF-alpha is a transcription factor that modulates a wide range of processes, including erythropoiesis, angiogenesis, and cellular metabolism. We describe a family with erythrocytosis and a mutation in the HIF2A gene, which encodes the HIF-2alpha protein. Our functional studies indicate that this mutation leads to stabilization of the HIF-2alpha protein and suggest that wild-type HIF-2alpha regulates erythropoietin production in adults.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Eritropoyesis/genética , Eritropoyetina/biosíntesis , Mutación Puntual , Policitemia/genética , Adulto , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Análisis Mutacional de ADN , Femenino , Genotipo , Hematócrito , Hemoglobinas/análisis , Humanos , Masculino , Linaje , Policitemia/metabolismo , Reacción en Cadena de la PolimerasaRESUMEN
Two distinct groups of chronic lymphocytic leukaemia (CLL) are distinguished by the presence or absence of somatic hypermutation of the immunoglobulin heavy-chain gene. CLL without somatic hypermutation has an adverse outcome, but the precise biological differences that underlie this more aggressive clinical-course are unclear. Using a proteomic approach, we found that the two prognostic forms of CLL were consistently distinguished according to their protein expression pattern. The most important difference observed related to the different expression of nucleophosmin 1 between the two forms of CLL. This different expression was not related to apoptosis, proliferation or gene mutation. However, co-immunoprecipitation experiments identified an association between nucleophosmin 1 and ribosomal proteins. Using immunocytofluorescence, nucleophosmin 1 expression was identified in the nucleoli and nucleoplasm of all cells, but in a proportion of cells, nucleophosmin had been transferred from the nucleoplasm to the cytoplasm. Both the fluorescent intensity, and the frequency of cytoplasmic nucleophosmin 1 expression, was higher in CLL without somatic hypermutation. We propose therefore, that nucleophosmin 1, in association with ribosomal proteins, undergoes nucleo-cytoplasmic shuttling in CLL. This process is most prominent in un-mutated CLL and may signify altered protein biosynthesis.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Diagnóstico Diferencial , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Nucleofosmina , Pronóstico , Hipermutación Somática de Inmunoglobulina , Regulación hacia ArribaRESUMEN
Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell disease, associated with a t(9, 22) chromosomal translocation leading to formation of the BCR/ABL chimeric protein, which has an intrinsic tyrosine kinase activity. Recently, the BCR/ABL tyrosine kinase inhibitor imatinib mesylate (imatinib) has been successfully used clinically, although, disease relapse can still occur. The precise detail of the mechanism by which CML cells respond to imatinib is still unclear. We therefore systematically examined the effects of imatinib on the primitive CML cell proteome, having first established that the drug inhibits proliferation and induces increased apoptosis and differentiation. To define imatinib-induced effects on the CML proteome, we employed isobaric tag peptide labeling (iTRAQ) coupled to two-dimensional liquid chromatography/tandem mass spectrometry. Given the limited clinical material available, the isobaric tag approach identified a large population of proteins and provided relative quantification on four samples at once. Novel consequences of the action of imatinib were identified using this mass spectrometric approach. DEAD-box protein 3, heat shock protein 105 kDa, and peroxiredoxin-3 were identified as potential protein markers for response to imatinib.
Asunto(s)
Antineoplásicos/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteoma/efectos de los fármacos , Proteómica/métodos , Pirimidinas/farmacología , Apoptosis , Benzamidas , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromatografía Liquida/métodos , ARN Helicasas DEAD-box/análisis , Proteínas del Choque Térmico HSP110/análisis , Células Madre Hematopoyéticas/metabolismo , Humanos , Mesilato de Imatinib , Péptidos/química , Peroxidasas/análisis , Peroxiredoxina III , Peroxirredoxinas , Proteoma/análisis , Espectrometría de Masas en Tándem/métodos , Células Tumorales CultivadasRESUMEN
PURPOSE: To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival. PATIENTS AND METHODS: Ninety-one previously treated patients with CLL (74 men and 17 women; median age, 58 years [range, 32 to 75 years]; 44 were refractory to purine analogs) received a median of 9 weeks of alemtuzumab treatment between 1996 and 2003. Regular bone marrow assessments by MRD flow cytometry were performed with the aim of eradicating detectable MRD (< 1 CLL cell in 10(5) normal cells). RESULTS: Responses according to National Cancer Institute-sponsored working group response criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 patients (19%), and no response (NR) in 42 patients (46%). Twenty-two (50%) of 44 purine analog-refractory patients responded to alemtuzumab. Detectable CLL was eradicated from the blood and marrow in 18 patients (20%). Median survival was significantly longer in MRD-negative patients compared with those achieving an MRD-positive CR, PR, or NR. Patients achieving an MRD-negative CR had a longer treatment-free survival than patients with MRD-positive CRs, PR, or NR: MRD-negative CRs, not reached; MRD-positive CRs, 20 months; PRs, 13 months; NR, 6 months (P < .0001). Overall survival for the 18 patients with MRD-negative remissions was 84% at 60 months. Eight (47%) of the MRD-negative patients converted to MRD positivity at a median of 28 months. CONCLUSION: MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Neoplasia Residual , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Médula Ósea/patología , Supervivencia sin Enfermedad , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Médula Ósea/metabolismo , Linfoma de Burkitt/genética , Linfoma de Burkitt/patología , Adulto , Anciano , Antineoplásicos/uso terapéutico , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/tratamiento farmacológico , Citogenética , Femenino , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Resultado del TratamientoAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Trasplante de Células Madre/métodos , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Recurrencia , Análisis de Supervivencia , Adulto JovenRESUMEN
INTRODUCTION: T-cell prolymphocytic leukaemia is a rare condition that constitutes around 2% of cases of small lymphocytic leukaemia in adults. It follows an aggressive clinical course with a poor prognosis. CASE PRESENTATION: We report a 55-year-old male who was diagnosed with T-cell prolymphocytic leukaemia following investigations for microscopic haematuria. Splenomegaly was identified on a plain abdominal radiograph and intravenous urography, thus triggering further investigations and diagnosis. CONCLUSION: Our case-report serves to remind us of the need to bear in mind other possible pathologies outwith our own area of expertise when interpreting results of any kind. This is perhaps increasingly important in the current era of increasing sub-specialisation throughout medicine.
RESUMEN
Campath-1H (alemtuzumab) is the most effective monoclonal antibody in single-agent use in B-cell chronic lymphocytic leukemia (CLL) with reported response rates of 33% to 70%. Combination therapy is now the conventional treatment for most hematologic malignancies. Monoclonal antibody treatments may sensitize tumor cells to subsequent chemotherapy. We report the combination of Campath-1H with fludarabine in patients with CLL refractory to each agent used singly. Six patients who had received a median of 8 courses of fludarabine (range, 4-10 courses) and 16 weeks of Campath-1H (range, 8-32 weeks) were treated. Five patients responded, including one who had a complete response by National Cancer Institute criteria. The responses observed were better in each patient than responses after each agent used singly. Complete morphologic bone marrow responses were seen in 3 patients, including eradication of disease measured by sensitive flow cytometry in 2. Campath-1H combined with fludarabine is a highly promising novel therapy for refractory CLL.