RESUMO
Core binding factor (CBF) participates in specification of the hematopoietic stem cell and functions as a critical regulator of hematopoiesis. Translocation or point mutation of acute myeloid leukemia 1 (AML1)/RUNX1, which encodes the DNA-binding subunit of CBF, plays a central role in the pathogenesis of acute myeloid leukemia and myelodysplasia. We characterized the t(X;21)(p22.3;q22.1) in a patient with myelodysplasia that fuses AML1 in-frame to the novel partner gene FOG2/ZFPM2. The reciprocal gene fusions AML1-FOG2 and FOG2-AML1 are both expressed. AML1-FOG2, which fuses the DNA-binding domain of AML1 to most of FOG2, represses the transcriptional activity of both CBF and GATA1. AML1-FOG2 retains a motif that recruits the corepressor C-terminal binding protein (CtBP) and these proteins associate in a protein complex. These results suggest a central role for CtBP in AML1-FOG2 transcriptional repression and implicate coordinated disruption of the AML1 and GATAdevelopmental programs in the pathogenesis of myelodysplasia.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Síndromes Mielodisplásicas/genética , Proteínas de Fusão Oncogênica/genética , Fosfoproteínas/metabolismo , Oxirredutases do Álcool , Fator de Ligação a CCAAT/genética , Cromossomos Humanos Par 21 , Cromossomos Humanos X , Subunidade alfa 2 de Fator de Ligação ao Core , Proteínas de Ligação a DNA/genética , Fatores de Ligação de DNA Eritroide Específicos , Fator de Transcrição GATA1 , Humanos , Síndromes Mielodisplásicas/etiologia , Proteínas de Fusão Oncogênica/metabolismo , Ligação Proteica , Proteínas Repressoras , Fatores de Transcrição/genética , Transcrição Gênica , Translocação GenéticaRESUMO
PURPOSE: Analysis of patients with late relapse (LR) of germ cell tumor (GCT) with reports on clinical characteristics, outcomes, and molecular and cytogenetic features. PATIENTS AND METHODS: Eighty-three patients evaluated at Indiana University from 1993 through 2000 for relapse of GCT more than 2 years from initial therapy were reviewed. Available specimens were investigated for expression of the transcription regulator FoxD3 and apurinic/apyrimidinic endonuclease and the presence of chromosome 12 abnormalities. RESULTS: Median interval from initial presentation to LR was 85 months. Forty-three of 49 LR patients who underwent surgery were rendered disease free (NED), and 20 (46.5%) remain continuously NED. Thirty-two patients received chemotherapy, but only six (18.8%) obtained a complete remission. Five of these patients remain continuously NED after chemotherapy alone, including three who were chemotherapy naïve. Eighteen of these 32 patients were successfully rendered NED by postchemotherapy surgery, and 12 remain continuously NED. Two patients continue on observation with no treatment for their LR. Overall, 69 of the 81 treated patients (85.2%) ultimately achieved an NED state, and 38 (46.9%) remain continuously NED with median follow-up from LR therapy of 24.5 months (range, 1 to 83 months), whereas nine other patients are currently NED after therapy for subsequent relapses. Because of the small numbers of specimens tested, we were unable to draw any definitive conclusions from the molecular and cytogenetic analyses. CONCLUSION: GCT patients require lifetime follow-up. At the time of LR, surgical resection alone remains our preferred therapy.