RESUMO
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.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Dióxido de Carbono/sangue , Fenômenos Fisiológicos Cardiovasculares/genética , Regulação da Expressão Gênica/fisiologia , Oxigênio/sangue , Doença de von Hippel-Lindau/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/sangue , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Estudos de Casos e Controles , Teste de Esforço , Feminino , Humanos , Masculino , Mutação , Doença de von Hippel-Lindau/sangue , Doença de von Hippel-Lindau/genéticaRESUMO
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.
Assuntos
Biomarcadores Tumorais/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Análise Mutacional de DNA/métodos , DNA de Neoplasias/genética , Diagnóstico Diferencial , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Nucleofosmina , Prognóstico , Hipermutação Somática de Imunoglobulina , Regulação para CimaAssuntos
Medula Óssea/metabolismo , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/tratamento farmacológico , Citogenética , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Resultado do TratamentoRESUMO
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.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Transplante de Células-Tronco/métodos , Adulto , Idoso , Alemtuzumab , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Recidiva , Análise de Sobrevida , Adulto JovemRESUMO
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.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Eritropoese/genética , Eritropoetina/biossíntese , Mutação Puntual , Policitemia/genética , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Análise Mutacional de DNA , Feminino , Genótipo , Hematócrito , Hemoglobinas/análise , Humanos , Masculino , Linhagem , Policitemia/metabolismo , Reação em Cadeia da PolimeraseRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteoma/efeitos dos fármacos , Proteômica/métodos , Pirimidinas/farmacologia , Apoptose , Benzamidas , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida/métodos , RNA Helicases DEAD-box/análise , Proteínas de Choque Térmico HSP110/análise , Células-Tronco Hematopoéticas/metabolismo , Humanos , Mesilato de Imatinib , Peptídeos/química , Peroxidases/análise , Peroxirredoxina III , Peroxirredoxinas , Proteoma/análise , Espectrometria de Massas em Tandem/métodos , Células Tumorais CultivadasAssuntos
Hemoglobinúria Paroxística/complicações , Vasculite por IgA/etiologia , Adulto , Feminino , Fibrinolíticos/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/patologia , Humanos , Vasculite por IgA/tratamento farmacológico , Vasculite por IgA/patologia , Necrose , Proteína C/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Pele/patologia , Trombose/complicações , Trombose/patologiaRESUMO
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.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Neoplasia Residual , Adulto , Idoso , Alemtuzumab , Anticorpos Monoclonais Humanizados , Medula Óssea/patologia , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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.