DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding

Blood. 2013 Jan 3;121(1):178-87. doi: 10.1182/blood-2012-08-448860. Epub 2012 Nov 14.


The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic acid receptor α (PML-RARα) in establishing these patterns. Cells from APL patients showed increased genome-wide DNA methylation with higher variability than healthy CD34(+) cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes. Transcription factor-binding sites (eg, the c-myc-binding sites) were associated with low methylation. However, SUZ12- and REST-binding sites identified in embryonic stem cells were preferentially DNA hypermethylated in APL cells. Unexpectedly, PML-RARα-binding sites were also protected from aberrant DNA methylation in APL cells. Consistent with this, myeloid cells from preleukemic PML-RARα knock-in mice did not show altered DNA methylation and the expression of PML-RARα in hematopoietic progenitor cells prevented differentiation without affecting DNA methylation. Treatment of APL blasts with all-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα-mediated initiation of leukemogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Chromosomes, Human / ultrastructure
  • CpG Islands
  • DNA Methylation*
  • DNA, Neoplasm / genetics*
  • DNA, Neoplasm / metabolism
  • Disease Progression
  • Gene Expression Regulation, Leukemic*
  • Gene Knock-In Techniques
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Leukemia, Promyelocytic, Acute / drug therapy
  • Leukemia, Promyelocytic, Acute / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins / physiology
  • Neoplastic Stem Cells / metabolism
  • Oncogene Proteins, Fusion / physiology
  • Phenotype
  • Polycomb Repressive Complex 2 / metabolism
  • Preleukemia / genetics
  • Recombinant Fusion Proteins / physiology
  • Repressor Proteins / metabolism
  • Transcription Factors / metabolism*
  • Tretinoin / therapeutic use


  • DNA, Neoplasm
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • RE1-silencing transcription factor
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • SUZ12 protein, human
  • Transcription Factors
  • promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
  • Tretinoin
  • Polycomb Repressive Complex 2