Downregulation of circadian clock genes in chronic myeloid leukemia: alternative methylation pattern of hPER3

Cancer Sci. 2006 Dec;97(12):1298-307. doi: 10.1111/j.1349-7006.2006.00331.x. Epub 2006 Sep 25.


Disruption of circadian rhythm is believed to play a critical role in cancer development. To gain further insights into the roles of circadian genes in chronic myeloid leukemia (CML), we analyzed peripheral blood from 53 healthy individuals and 35 CML patients for the expression of the nine circadian genes. The expression levels of hPER1, hPER2, hPER3, hCRY1, hCRY2 and hBMAL1 were significantly impaired in both chronic phase and blastic crisis of CML cases compared with those in healthy individuals (P < 0.001). Methylation studies in the promoter areas of these six genes revealed that only the CpG sites of the hPER3 gene were methylated in all of the CML patients, and the methylated CpG frequencies differed significantly in patients at blastic crisis (8.24 +/- 0.73) or at chronic phase (4.48 +/- 0.48). The CpG sites of the hPER2 gene were also methylated in 40% of the CML patients. No mutation was found within the coding region of hPER3 in CML cases. Our results suggest that the downregulated hPER3 expression in CML is correlated with the inactivation of hPER3 by methylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors
  • Adult
  • Azacitidine
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Blast Crisis / genetics
  • CLOCK Proteins
  • Cell Cycle Proteins / genetics
  • Circadian Rhythm / genetics*
  • Cryptochromes
  • DNA Methylation*
  • Down-Regulation
  • Flavoproteins / genetics
  • Gene Expression Regulation, Leukemic*
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Mutation / genetics
  • Nuclear Proteins / genetics*
  • Period Circadian Proteins
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic / genetics
  • Trans-Activators / genetics*
  • Transcription Factors / genetics*


  • ARNTL Transcription Factors
  • ARNTL protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Cryptochromes
  • Flavoproteins
  • Nuclear Proteins
  • PER1 protein, human
  • PER2 protein, human
  • PER3 protein, human
  • Period Circadian Proteins
  • Trans-Activators
  • Transcription Factors
  • CLOCK Proteins
  • CLOCK protein, human
  • Azacitidine