title: Deregulated expression of circadian clock and clock-controlled cell cycle genes in chronic lymphocytic leukemia.
abstract: Circadian rhythms are endogenous and self-sustained oscillations of multiple biological processes with approximately 24-h rhythmicity. Circadian genes and their protein products constitute the molecular components of the circadian oscillator that form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends from core clock genes to various clock-controlled genes that include various cell cycle genes. Aberrant expression of circadian clock genes, therefore, may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. The current study encompasses the investigation of simultaneous expression of four circadian clock genes (Bmal1, Clock, Per1 and Per2) and three clock-controlled cell cycle genes (Myc, Cyclin D1 and Wee1) at mRNA level and determination of serum melatonin levels in peripheral blood samples of 37 CLL (chronic lymphocytic leukemia) patients and equal number of age- and sex-matched healthy controls in order to indicate association between deregulated circadian clock and manifestation of CLL. Results showed significantly down-regulated expression of Bmal1, Per1, Per2 and Wee1 and significantly up-regulated expression of Myc and Cyclin D1 (P < 0.0001) in CLL patients as compared to healthy controls. When expression of these genes was compared between shift-workers and non-shift-workers within the CLL group, the expression was found more aberrant in shift-workers as compared to non-shift-workers. However, this difference was found statistically significant for Myc and Cyclin D1 only (P < 0.05). Serum melatonin levels were found significantly low (P < 0.0001) in CLL subjects as compared to healthy controls whereas melatonin levels were found still lower in shift-workers as compared to non-shift-workers within CLL group (P < 0.01). Our results suggest that aberrant expression of circadian clock genes can lead to aberrant expression of their downstream targets that are involved in cell proliferation and apoptosis and hence may result in manifestation of CLL. Moreover, shift-work and low melatonin levels may also contribute in etiology of CLL by further perturbing of circadian clock.
authors.affiliation: Department of Physiology & Cell Biology, University of Health Sciences, Lahore, Pakistan.
authors.forename: Sobia
authors.initials: S
authors.lastname: Rana
authors.forename: Mustafa
authors.initials: M
authors.lastname: Munawar
authors.forename: Adeela
authors.initials: A
authors.lastname: Shahid
authors.forename: Meera
authors.initials: M
authors.lastname: Malik
authors.forename: Hafeez
authors.initials: H
authors.lastname: Ullah
authors.forename: Warda
authors.initials: W
authors.lastname: Fatima
authors.forename: Shahida
authors.initials: S
authors.lastname: Mohsin
authors.forename: Saqib
authors.initials: S
authors.lastname: Mahmood
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D057906:Circadian Clocks; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics*; D008297:Male; D008550:Melatonin / Q000097:blood; D008875:Middle Aged; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; D056925:Circadian Rhythm Signaling Peptides and Proteins; D008550:Melatonin