title: Downregulation of circadian clock genes in chronic myeloid leukemia: alternative methylation pattern of hPER3.
abstract: 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.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Yang
authors.forename: Jan-Gowth
authors.initials: JG
authors.lastname: Chang
authors.forename: Pai-Mei
authors.initials: PM
authors.lastname: Lin
authors.forename: Kai-Ping
authors.initials: KP
authors.lastname: Tang
authors.forename: Yen-Hsu
authors.initials: YH
authors.lastname: Chen
authors.forename: Hugo You-Hsien
authors.initials: HY
authors.lastname: Lin
authors.forename: Ta-Chih
authors.initials: TC
authors.lastname: Liu
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Hsiao
authors.forename: Yi-Chang
authors.initials: YC
authors.lastname: Liu
authors.forename: Sheng-Fung
authors.initials: SF
authors.lastname: Lin
mesh_terms: D056930:ARNTL Transcription Factors; D000328:Adult; D001374:Azacitidine; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001752:Blast Crisis / Q000235:genetics; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D056931:Cryptochromes; D019175:DNA Methylation; D015536:Down-Regulation; D005420:Flavoproteins / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D056950:Period Circadian Proteins; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D056930:ARNTL Transcription Factors; D001374:Azacitidine; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D005420:Flavoproteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C539022:PER1 protein, human; C421902:PER2 protein, human; C512644:PER3 protein, human; C538943:CLOCK protein, human