Down-regulation of EVI1 is associated with epigenetic alterations and good prognosis in patients with acute myeloid leukemia
Por:
Vazquez, I, Maicas, M, Cervera, J, Agirre, X, Marin-Bejar, O, Marcotegui, N, Vicente, C, Lahortiga, I, Gomez-Benito, M, Carranza, C, Valencia, A, Brunet, S, Lumbreras, E, Prosper, F, Gomez-Casares, MT, Hernandez-Rivas, JM, Calasanz, MJ, Sanz, MA, Sierra, J, Odero, MD
Publicada:
1 oct 2011
Resumen:
Background
The EVI1 gene (3q26) codes for a zinc finger transcription factor with important roles in both mammalian development and leukemogenesis. Over-expression of EVI1 through either 3q26 rearrangements, MLL fusions, or other unknown mechanisms confers a poor prognosis in acute myeloid leukemia.
Design and Methods
We analyzed the prevalence and prognostic impact of EVI1 over-expression in a series of 476 patients with acute myeloid leukemia, and investigated the epigenetic modifications of the EVI1 locus which could be involved in the transcriptional regulation of this gene.
Results
Our data provide further evidence that EVI1 over-expression is a poor prognostic marker in acute myeloid leukemia patients less than 65 years old. Moreover, we found that patients with no basal expression of EVI1 had a better prognosis than patients with expression/over-expression (P=0.036). We also showed that cell lines with over-expression of EVI1 had no DNA methylation in the promoter region of the EVI1 locus, and had marks of active histone modifications: H3 and H4 acetylation, and trimethylation of histone H3 lysine 4. Conversely, cell lines with no expression of EVI1 have DNA hypermethylation and are marked by repressive trimethylation of histone H3 lysine 27 at the EVI1 promoter.
Conclusions
Our results identify EVI1 over-expression as a poor prognostic marker in a large, independent cohort of acute myeloid leukemia patients less than 65 years old, and show that the total absence of EVI1 expression has a prognostic impact on the outcome of such patients. Furthermore, we demonstrated for the first time that an aberrant epigenetic pattern involving DNA methylation, H3 and H4 acetylation, and trimethylation of histone H3 lysine 4 and histone H3 lysine 27 might play a role in the transcriptional regulation of EVI1 in acute myeloid leukemia. This study opens new avenues for a better understanding of the regulation of EVI1 expression at a transcriptional level.
Filiaciones:
Vazquez, I:
Univ Navarra, CIMA, Div Oncol, Pamplona 31008, Spain
Maicas, M:
Univ Navarra, CIMA, Div Oncol, Pamplona 31008, Spain
Univ Navarra, Dept Genet, Pamplona 31008, Spain
Cervera, J:
Univ Hosp La Fe, Valencia, Spain
Agirre, X:
Univ Navarra, CIMA, Div Oncol, Pamplona 31008, Spain
Marin-Bejar, O:
Univ Navarra, CIMA, Div Oncol, Pamplona 31008, Spain
Marcotegui, N:
Univ Navarra, CIMA, Div Oncol, Pamplona 31008, Spain
Vicente, C:
Univ Navarra, CIMA, Div Oncol, Pamplona 31008, Spain
Lahortiga, I:
VIB, Dept Mol & Dev Genet, Human Genome Lab, Louvain, Belgium
Gomez-Benito, M:
Univ Navarra, CIMA, Div Oncol, Pamplona 31008, Spain
Carranza, C:
Inst Invest Genet, Milpas Altas, Guatemala
Valencia, A:
Univ Hosp La Fe, Valencia, Spain
Brunet, S:
Hosp Santa Creu & Sant Pau, Barcelona, Spain
Lumbreras, E:
Univ Salamanca, Hosp Univ Salamanca, E-37008 Salamanca, Spain
Univ Salamanca, CSIC, E-37008 Salamanca, Spain
Prosper, F:
Univ Navarra, CIMA, Div Oncol, Pamplona 31008, Spain
Gomez-Casares, MT:
Hosp Dr Negrin, Las Palmas Gran Canaria, Spain
Hernandez-Rivas, JM:
Univ Salamanca, Hosp Univ Salamanca, E-37008 Salamanca, Spain
Univ Salamanca, CSIC, E-37008 Salamanca, Spain
Calasanz, MJ:
Univ Navarra, Dept Genet, Pamplona 31008, Spain
Sanz, MA:
Univ Hosp La Fe, Valencia, Spain
Sierra, J:
Hosp Santa Creu & Sant Pau, Barcelona, Spain
Odero, MD:
Univ Navarra, CIMA, Div Oncol, Pamplona 31008, Spain
Univ Navarra, Dept Genet, Pamplona 31008, Spain
Gold, Green Published
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