Circadian Rhythm Dysregulation and Leukemia Development: The Role of Clock Genes as Promising Biomarkers

Abstract

The circadian clock (CC) is a daily system that regulates the oscillations of physiological processes and can respond to the external environment in order to maintain internal homeostasis. For the functioning of the CC, the clock genes (CG) act in different metabolic pathways through the clock-controlled genes (CCG), providing cellular regulation. The CC's interruption can result in the development of different diseases, such as neurodegenerative and metabolic disorders, as well as cancer. Leukemias correspond to a group of malignancies of the blood and bone marrow that occur when alterations in normal cellular regulatory processes cause the uncontrolled proliferation of hematopoietic stem cells. This review aimed to associate a deregulated CC with the manifestation of leukemia, looking for possible pathways involving CG and their possible role as leukemic biomarkers.

Keywords: biomarkers; cell cycle; circadian rhythm; clock genes; leukemia.

Figure 1

Clock-BMAL1 complex activity during a day cycle. At sunrise, CLOCK-BMAL1 promotes the beginning of the circadian clock by binding to the enhancer box (E-box) regions of target circadian clock genes (CG) and increasing their transcription. During the day, the cellular levels of clock proteins such as PER 1/2/3, CRY 1/2, TIM, and REV-ERB continue to rise; at the day’s end, their association with casein kinase 1 epsilon (CK1ε) facilitates transportation into the cell nucleus, where circadian clock gene proteins have a negative feedback effect on the activity of the CLOCK-BMAL1 complex. The suppressive effect of the PER-CRY-CK1ε complex on transcription factors leads to their inhibition of their own transcription, and a consequent decrease in the complex’s cell levels during the night and until dawn, after which the activity of CLOCK-BMAL1 is once again unimpaired, and the circadian clock restarts. Created with BioRender.com.

Figure 2

Role of clock genes in leukemic transformation. The CLOCK-BMAL1 complex promotes the expression of clock genes and changes in the circadian clock. Furthermore, at high expression levels, CLOCK-BMAL1 can directly affect Wee1, which phosphorylates CDK1/cyclin B, interfering at the cell cycle transition from the G2 to the M phase. In addition, some circadian clock genes were reported at low levels, represented in yellow as PER, which altered the expression of cMyc, which is closely linked to cyclin D1. This also happens with NAPS2, which affects cMyc-Cyclin D1, leaving it overactivated. Cry1 presents a low-level expression that directly affects the expression of p21 and pro-inflammatory cytokines such as TNF-α and IL-6. Also at low expression levels, Cry2 can affect cMyc expression, which again supports its overactivity. In addition, Cry2 also affects p53 expression. Low levels of REV-ERBα and PPARα can also be correlated with changes in p21 expression. Furthermore, the REV-ERBα gene can also inhibit the cell cycle transition from the G1 to the S phase. The SHARP1 at high expression levels, as represented in green, has a correlation with the negative expression of CLOCK-BMAL1. The TIMELESS gene is also an important molecular biomarker, which—according to the studies—can present a high or low expression, participate in cell cycle checkpoints, and regulate Chk1 and Chk2, so it can cause an interruption in the G0 and G1 phases of the cell cycle. Finally, another gene that was shown to be at high and low levels was the CKIε gene, which—at its high levels—plays a role in the phosphorylation of the PER gene. Created with BioRender.com.