Table 1.
Studies on the involvement of clock genes in leukemia pathogenesis, from the past 10 years.
| Gene | Type of Samples Analyzed | Function | Expression Levels | Reference |
|---|---|---|---|---|
| BMAL1 | 37 Blood samples from chronic lymphocytic leukemia. Patients and healthy controls | It forms a heterodimer with CLOCK and NPAS2. This heterodimer binds to E-box enhancing elements upstream of the Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2), activating the transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/BMAL1 or NPAS2/BMAL1 complexes. | Significantly downregulated in CLL patients as compared to their healthy controls. Not significantly altered in shift-workers as compared to non-shift-workers within the CLL group. |
[89] |
| PER1 | Encodes components of the circadian rhythms of locomotor activity, metabolism, and behavior. | |||
| PER2 | ||||
| NPAS2 (rs2305160) | Blood sample of 74 individuals including 37 diagnosed cases of CLL | Probable involvement of NPAS2 in tumorigenesis, by regulating PER2 that can act as a tumor suppressor. | No significant association of rs2305160 polymorphism of NPAS2 gene with melatonin levels in any of the CLL groups. | [90] |
| PER1 | Peripheral blood samples of 51 healthy adult volunteers, 44 patients newly-diagnosed with AML, and 23 newly–diagnosed with ALL | Encodes components of the circadian rhythms of locomotor activity, metabolism, and behavior. | Upregulated in patients with AM, who achieved remission, but remained low in patients whose disease relapsed after treatment. Downregulated in PB leukocytes in patients with AML when compared to those from healthy individuals. |
[91] |
| PER2 | Downregulated in PB leukocytes in patients with AML when compared to those from healthy individuals. | |||
| PER3 | Encodes components of the circadian rhythms of locomotor activity, metabolism, and behavior. | Upregulated in patients with ALL who achieved remission but remained low in patients whose disease relapsed after treatment. Downregulated in PB leukocytes in patients with AML when compared to those from healthy individuals. In patients with ALL, the expression levels were downregulated |
||
|
TIM (Timeless) |
The protein encoded by this gene is highly conserved and is involved in cell survival after damage or stress, increase in DNA polymerase epsilon activity, maintenance of telomere length, and epithelial cell morphogenesis. The encoded protein also plays a role in the circadian rhythm autoregulatory loop, interacting with the PERIOD genes (PER1, PER2, and PER3) and others to downregulate activation of PER1 by CLOCK/BMAL1. | Downregulated in PB leukocytes in patients with AML when compared to those from healthy individuals. Upregulated in PB leukocytes in patients with ALL when compared to healthy individuals |
||
| CRY1 | This gene encodes a flavin adenine dinucleotide-binding protein that is a key component of the circadian core oscillator complex, which regulates the circadian clock | Downregulated in PB leukocytes in patients with AML when compared to those from healthy individuals. In patients with ALL, the expression levels were downregulated |
||
| CRY2 | Downregulated in PB leukocytes in patients with AML when compared to those from healthy individuals | |||
| BMAL1 | It forms a heterodimer with CLOCK and BMAL1. This heterodimer binds to E-box enhancing elements upstream of the Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates the transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/BMAL1 or NPAS2/BMAL1 complexes | |||
| CKIε | Has been implicated in the control of cytoplasmic and nuclear processes, including DNA replication and repair. The encoded protein is found in the cytoplasm as a monomer and can phosphorylate a variety of proteins, including itself. This protein has been shown to phosphorylate the period (PER), a circadian rhythm protein. | Upregulated in PB leukocytes in patients with AML, when compared to those from healthy individuals. Upregulated in PB leukocytes in patients with ALL when Compared to healthy individuals |
||
| PER2 | Peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood samples collected from 26 AML patients, 22 ALL patients, 13 CML patients, 14 CLL patients, and 30 healthy donors | Encodes components of the circadian rhythms of locomotor activity, metabolism, and behavior. | Downregulation in newly diagnosed patients with AML and patients with relapse of the disease, compared to controls. Downregulation in newly diagnosed and end of treatment from ALL patients compared to controls. Downregulation in CML patients compared with healthy controls. Downregulation in CLL patients compared with healthy controls. |
[92] |
| BMAL1 | It forms a heterodimer with CLOCK and NPAS2. This heterodimer binds to E-box enhancing elements upstream of the Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates the transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/BMAL1 or NPAS2/BMAL1 complexes. | Downregulation in newly diagnosed patients with AML and with relapse of the disease, compared to controls. Downregulation in newly diagnosed and end of treatment from ALL patients compared to controls. Downregulation in newly diagnosed CML patients compared with healthy controls. Downregulation in CLL patients compared with healthy controls. |
||
| CRY1 | This gene encodes a flavin adenine dinucleotide-binding protein that is a key component of the circadian core oscillator complex, which regulates the circadian clock | Downregulation in patients upon completion of treatment for AML and with relapse of the disease, compared to controls. Downregulation in newly diagnosed and end of treatment from ALL patients compared to controls. Downregulation in newly diagnosed CML patients compared with healthy controls. Downregulation in CLL patients compared with healthy controls. |
||
| CRY2 | Downregulation in newly diagnosed AML patients and patients upon completion of treatment for AML, and upregulation in patients with relapse of the disease, compared to controls. Downregulation in newly diagnosed and end of treatment from ALL patients compared to controls. Upregulation in CML patients upon 3-months course of chemotherapy, compared with healthy controls. |
|||
| CLOCK | The protein encoded by this gene plays a central role in the regulation of circadian rhythms. The protein encodes a transcription factor of the basic helix-loop-helix (bHLH) family and contains DNA binding histone acetyltransferase activity. The encoded protein forms a heterodimer with BMAL1 that binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes | Downregulation in patients with AML, compared to controls. Downregulation in patients newly diagnosed with ALL compared to controls. Downregulation in newly diagnosed CML patients compared with healthy controls. Downregulation in CLL patients at the end of treatment, compared with healthy controls. |
||
| REV-ERB α | This gene encodes a transcription factor that is a member of the nuclear receptor subfamily 1. The encoded protein is a ligand-sensitive transcription factor that negatively regulates the expression of core clock proteins. This protein represses BMAL1. This protein may also be involved in regulating genes that function in metabolic, inflammatory, and cardiovascular processes. | Downregulation in patients with AML compared with healthy samples. Downregulation in newly diagnosed and end of treatment from ALL patients compared to controls. Downregulation in newly diagnosed CML patients compared with healthy controls. Downregulation in CLL patients compared with healthy controls. |
||
| PPAR α | PPARs affect the expression of target genes involved in cell proliferation, cell differentiation, and immune and inflammation responses. | Downregulation in newly diagnosed and end treatment from AML patients compared to samples from healthy individuals. Downregulation in newly diagnosed and end of treatment from ALL patients compared to controls. Downregulation in newly diagnosed CML patients compared with healthy controls. |
||
| CRY-1 | PB and BM samples were collected from 100 CLL patients | This gene encodes a flavin adenine dinucleotide-binding protein that is a key component of the circadian core oscillator complex, which regulates the circadian clock | 40 CLL patients showed up-regulation of CRY-1 54 CLL patients showed down-regulation of CRY-1 6 CLL patients had undetectable CRY-1 expression |
[93] |
| SHARP1 (BHLHE41 or DEC2) | ML-2 cell line derived from a patient with AML; and 14 cases of MLL-AF6 and 42 cases of other subtypes of MLL-rearranged AMLs | This gene is a basic helix-loop-helix transcription factor that acts as a transcription repressor of clock genes and clock-controlled genes. | Up-regulated in MLL-AF6 AML patients compared to cases of other subtypes of AML and cases of normal BM CD34+ cells | [94] |
| NPAS2 | Two AML cell lines (MV4-11 and MOLM-14); and human hematopoietic cells from 34 AML patients and 16 healthy controls | This gene is a transcription factor that encodes a protein which will heterodimer with BMAL1 and form core circadian clock genes. | Upregulated in both AML cell lines and in AML patients, compared to controls | [95] |
| PER2 | Neutrophils isolated from the peripheral blood samples collected from 30 CML patients and 30 healthy donors | Encodes components of the circadian rhythms of locomotor activity, metabolism, and behavior. | Downregulated in patients with CML compared with healthy individuals | [96] |
ALL: Acute Lymphocytic Leukemia; AML: Acute Myeloid Leukemia; BM: Bone Marrow; CLL: Chronic Lymphocytic Leukemia; CML: Chronic Myeloid Leukemia; PB: Peripheral Blood.