RESUMO
The objective was to evaluate the prognostic impact of pre-transplant minimal residual disease (MRD) as determined by real-time quantitative polymerase chain reaction in 67 adult NPM1-mutated acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-eight of the 67 patients had a FLT3-ITD (42%). Median age at transplantation was 54.7 years, median follow-up for survival from time of allografting was 4.9 years. At transplantation, 31 patients were in first, 20 in second complete remission (CR) and 16 had refractory disease (RD). Pre-transplant NPM1 MRD levels were measured in 39 CR patients. Overall survival (OS) for patients transplanted in CR was significantly longer as compared to patients with RD (P=0.004), irrespective of whether the patients were transplanted in first or second CR (P=0.74). There was a highly significant difference in OS after allogeneic HSCT between pre-transplant MRD-positive and MRD-negative patients (estimated 5-year OS rates of 40 vs 89%; P=0.007). Multivariable analyses on time to relapse and OS revealed pre-transplant NPM1 MRD levels >1% as an independent prognostic factor for poor survival after allogeneic HSCT, whereas FLT3-ITD had no impact. Notably, outcome of patients with pre-transplant NPM1 MRD positivity >1% was as poor as that of patients transplanted with RD.
Assuntos
Biomarcadores Tumorais , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Neoplasia Residual/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Biomarcadores , Medula Óssea/patologia , Feminino , Duplicação Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasia Residual/diagnóstico , Nucleofosmina , Cuidados Pré-Operatórios , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Sequências Repetitivas de Ácido Nucleico , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
We analyzed the transcriptional events involved in the T cell receptor (TcR)-alpha mRNA expression in a human lymphoblastic T-cell line CEM. CD3-negative and CD3-positive CEM subclones that either lack mature TcR-alpha mRNA or express TcR-alpha mRNA were used. Exposure of the TcR-alpha mRNA negative subclones to phorbol 12-myristate 13-acetate (PMA) was followed by 2- to 3-fold increase of transcription, indicating that PMA acts on a transcriptional level. No increase of transcription was observed after blocking protein synthesis with cycloheximide (CHX) or after sequential stimulation with CHX followed by PMA. On the posttranscriptional level, CHX as well as PMA induced a progressive stabilization of TcR-alpha mRNA in the nuclear compartment, which was independent of ongoing transcription. The half-life of the TcR-alpha mRNA upon stimulation was about 6 hours. The accumulation of mature TcR-alpha mRNA seemed to be controlled by nuclear events on a transcriptional as well as posttranscriptional level. The data imply that alterations of TcR-alpha gene transcription are dependent on protein synthesis. DNA-binding proteins enhance transcription and labile nuclear proteins target TcR-alpha mRNA for rapid turnover.