title: DNA methylation profiles and their relationship with cytogenetic status in adult acute myeloid leukemia.
abstract: BACKGROUND
  Aberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required.
  
  
  RESULTS
  We carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients.
  
  
  CONCLUSIONS
  Our study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signature.
authors.affiliation: Molecular Cytogenetics Group, Centro Nacional Investigaciones Oncologicas, Centro de Investigaciones de Enfermedades Raras, Madrid, Spain. salvarez@cnio.es
authors.forename: Sara
authors.initials: S
authors.lastname: Alvarez
authors.forename: Javier
authors.initials: J
authors.lastname: Suela
authors.forename: Ana
authors.initials: A
authors.lastname: Valencia
authors.forename: Agustín
authors.initials: A
authors.lastname: Fernández
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.forename: Felipe
authors.initials: F
authors.lastname: Prósper
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: Alba
authors.initials: A
authors.lastname: Maiques
authors.forename: Francesco
authors.initials: F
authors.lastname: Acquadro
authors.forename: Sandra
authors.initials: S
authors.lastname: Rodriguez Perales
authors.forename: María José
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: Jose
authors.initials: J
authors.lastname: Roman-Gómez
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: José
authors.initials: J
authors.lastname: Cervera
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Sanz
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Juan C
authors.initials: JC
authors.lastname: Cigudosa
mesh_terms: D000328:Adult; D002877:Chromosomes, Human / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D015514:Oncogene Proteins, Fusion; D025521:Tumor Suppressor Proteins
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