Assuntos
Fatores Imunológicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Lenalidomida , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
Refractory anaemia with ring sideroblasts (RARS) and marked thrombocytosis (RARS-T) is a provisional entity in the World Health Organisation 2008 classification and has previously been shown to have a high proportion of JAK2(V617F) (Janus Kinase 2) and SF3B1 (Splicing Factor 3B subunit 1) mutations. The purpose of the present study was to analyse the frequency of SF3B1 mutations in a large cohort of 111 patients with RARS-T and 33 patients with RARS and to explore the prognostic impact of SF3B1 mutational status on RARS-T. The frequency of SF3B1 mutations in RARS-T (96/111, 86.5%) and RARS (28/33, 84.8%) was similar. In RARS-T, median survival was better in SF3B1-mutated patients than in SF3B1-non-mutated patients (6.9 and 3.3 years, respectively, P=0.003). RARS can be differentiated from RARS-T by the frequency of JAK2(V617F) (0% vs 48.6%). In RARS-T patients, SF3B1 (P=0.021) and JAK2 mutations (P=0.016) were independent factors for a better prognosis. Altogether, our results confirm that RARS-T is an independent entity that should be recognised by the next World Health Organisation classification. The assessment of SF3B1 mutations is of prognostic interest in RARS-T patients. Younger age, JAK2(V617F) and SF3B1 mutations are the main predicting factors for survival in RARS-T.
Assuntos
Anemia Refratária/genética , Anemia Refratária/mortalidade , Janus Quinase 2/genética , Mutação , Fosfoproteínas/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/complicações , Anemia Refratária/diagnóstico , Anemia Sideroblástica/complicações , Mapeamento Cromossômico , Feminino , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Prognóstico , Fatores de Processamento de RNA , Trombocitose/complicações , Adulto JovemAssuntos
Anemia Refratária/genética , Janus Quinase 2/genética , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Trombopoetina/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Sistema de RegistrosRESUMO
Since de-novo synthesis of pyrimidine nucleotides is coupled to the mitochondrial respiratory chain (RC) via dehydroorotic acid dehydrogenase (DHODH), respiratory chain dysfunction should impair pyrimidine synthesis. To investigate this, we used specific RC inhibitors, Antimycin A and Rotenone, to treat primary human keratinocytes and 143B cells, a human osteosarcoma cell line, in culture. This resulted in severe impairment of de novo pyrimidine nucleotide synthesis. The effects of RC inhibition were not restricted to pyrimidine synthesis, but concerned purine nucleotides, too. While the total amount of purine nucleotides was not diminished, they were significantly broken down from triphosphates to monophosphates, reflecting impaired mitochondrial ATP regeneration. The effect of Rotenone was similar to that of Antimycin A. This was surprising since Rotenone inhibits complex I of the respiratory chain, which is upstream of ubiquinone where DHODH interacts with the RC. In order to avoid unspecific effects of Rotenone, we examined the consequences of a mitochondrial DNA mutation that causes a specific complex I defect. The effect was much less pronounced than with Rotenone, suggesting that complex I inhibiton cannot fully explain the marked effect of Rotenone on pyrimidine nucleotide synthesis.