Downregulation of circadian clock genes in chronic myeloid leukemia: alternative methylation pattern of hPER3.
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.
Yang
Ming-Yu
MY
Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
Chang
Jan-Gowth
JG
Lin
Pai-Mei
PM
Tang
Kai-Ping
KP
Chen
Yen-Hsu
YH
Lin
Hugo You-Hsien
HY
Liu
Ta-Chih
TC
Hsiao
Hui-Hua
HH
Liu
Yi-Chang
YC
Lin
Sheng-Fung
SF
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*
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