PLoS ONE (Aug 2010)

DNA methylation profiles and their relationship with cytogenetic status in adult acute myeloid leukemia.

  • Sara Alvarez,
  • Javier Suela,
  • Ana Valencia,
  • Agustín Fernández,
  • Mark Wunderlich,
  • Xabier Agirre,
  • Felipe Prósper,
  • José Ignacio Martín-Subero,
  • Alba Maiques,
  • Francesco Acquadro,
  • Sandra Rodriguez Perales,
  • María José Calasanz,
  • Jose Roman-Gómez,
  • Reiner Siebert,
  • James C Mulloy,
  • José Cervera,
  • Miguel Angel Sanz,
  • Manel Esteller,
  • Juan C Cigudosa

DOI
https://doi.org/10.1371/journal.pone.0012197
Journal volume & issue
Vol. 5, no. 8
p. e12197

Abstract

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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.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.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.