Expression Of Circadian Clock And Cell Cycle Genes In Chronic Lymphocytic Leukemia

Abstract

Circadian rhythms are endogenous, self-sustained oscillations of multiple biological processes with approximately 24-hr 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 beyond clock genes to involve various clock-controlled genes (CCGs) that include various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. The current study was carried out to gain further insights into the roles of circadian genes and their downstream targets (cell cycle genes) in chronic lymphocytic leukemia (CLL). We analyzed peripheral blood from 37 CLL patients and equal number of their age- and sex-matched healthy controls for the expression of the four circadian clock and three cell cycle genes. The expression levels of BMAL1, PER1, PER2,MYC, CYCLIN D1 and WEE1 were significantly impaired in CLL cases compared with those in healthy individuals (P < 0.001). BMAL1, PER1, PER2 and WEE1 were found down regulated whereas MYC and CYCLIN D1 were found upregulated. This implies that the deregulated expression of circadian clock genes through their influence on downstream clock-controlled cell cycle genes can play a role in the manifestation of CLL. Moreover, when expression levels of abovementioned genes were compared between shift workers and non-shift workers within the CLL group, the expression levels were more aberrant in shiftworkers compared to non-shift workers. This indicates that circadian dysregulation in terms of shift work may also be a contributing factor in the etiology of CLL. In the current study, serum melatonin levels were also determined in 37 CLL cases and their healthy controls. Serum melatonin levels were found significantly low (P<0.05) in CLL subjects as compared to healthy controls. Furthermore, melatonin levels were found still lower in shift workers as compared to non-shift workers within CLL group. Our results suggest that down regulation of BMAL1, PER1 and PER2 is related to upregulation of Cyclin D1, MYC and down regulation of WEE1 in CLL. Thus, aberrant expression of clock genes can lead to abnormal expression of downstream cell-cycle genes and play a role in the manifestation of CLL. Moreover, low melatonin levels in CLL patients may play a part in xivderegulation of circadian clock gene expression and shiftwork serves as a further contributing factor to an already perturbed circadian clock genes’ expression and low melatonin levels in CLL.