title: Down-regulation of EVI1 is associated with epigenetic alterations and good prognosis in patients with acute myeloid leukemia.
abstract: 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.
  
  
  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.
authors.affiliation: Division of Oncology, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Iria
authors.initials: I
authors.lastname: Vázquez
authors.forename: Miren
authors.initials: M
authors.lastname: Maicas
authors.forename: José
authors.initials: J
authors.lastname: Cervera
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.forename: Oskar
authors.initials: O
authors.lastname: Marin-Béjar
authors.forename: Nerea
authors.initials: N
authors.lastname: Marcotegui
authors.forename: Carmen
authors.initials: C
authors.lastname: Vicente
authors.forename: Idoya
authors.initials: I
authors.lastname: Lahortiga
authors.forename: Maria
authors.initials: M
authors.lastname: Gomez-Benito
authors.forename: Claudia
authors.initials: C
authors.lastname: Carranza
authors.forename: Ana
authors.initials: A
authors.lastname: Valencia
authors.forename: Salut
authors.initials: S
authors.lastname: Brunet
authors.forename: Eva
authors.initials: E
authors.lastname: Lumbreras
authors.forename: Felipe
authors.initials: F
authors.lastname: Prosper
authors.forename: María T
authors.initials: MT
authors.lastname: Gómez-Casares
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Hernández-Rivas
authors.forename: María J
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Sanz
authors.forename: Jorge
authors.initials: J
authors.lastname: Sierra
authors.forename: María D
authors.initials: MD
authors.lastname: Odero
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D045744:Cell Line, Tumor; D002893:Chromosomes, Human, Pair 3; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors