Body Clock Gene BMAL1 Plummets in Childhood Leukemia, Study Finds

Every cell in the human body carries an internal clock, a molecular timekeeper that orchestrates when genes switch on and off across the day and night. For decades, this circadian machinery was thought of mainly as a scheduling system for sleep, hormones, and metabolism. But a growing body of research now suggests that when the clock breaks down, the consequences can be far more sinister, including an increased vulnerability to cancer. A new study of children with acute myeloid leukemia adds a striking piece of evidence to that picture, reporting that two genes central to cellular timing and cell division control are dramatically silenced in the bone marrow of young patients.

The research, conducted by a team at Mashhad University of Medical Sciences in Iran and published in the journal Molecular Biology Reports, examined bone marrow samples from 40 children who had been newly diagnosed with acute myeloid leukemia, one of the most aggressive cancers of the blood and bone marrow. The investigators compared the expression levels of two genes, BMAL1 and WEE1, against samples from 20 non-malignant control subjects. BMAL1, also known by its alternate name ARNTL, is widely regarded as the engine of the molecular circadian clock, forming a transcriptional complex that drives rhythmic gene expression throughout the body. WEE1, by contrast, is a kinase that acts as a gatekeeper at the G2/M checkpoint of the cell cycle, holding cells back from entering mitosis when their DNA is damaged or replication is incomplete.

The results were unambiguous. Using real-time quantitative PCR to measure messenger RNA levels, the team found that both genes were expressed at significantly lower levels in the leukemic samples than in the healthy controls, with statistical significance reaching a P value of less than 0.001. The magnitude of the difference was substantial: relative expression of BMAL1 in the patients’ bone marrow was just 0.18-fold that of the control group, while WEE1 expression stood at 0.31-fold. In other words, the core clock gene had been reduced to less than a fifth of its normal activity, and the cell cycle checkpoint kinase to less than a third.

Perhaps the most intriguing finding emerged when the researchers looked at how gene expression related to clinical measurements. BMAL1 expression showed a significant negative correlation with both white blood cell count and blast percentage, the proportion of immature, leukemic cells in the bone marrow. The correlation coefficients were -0.440 for white blood cell count, with a P value of 0.004, and -0.418 for blast percentage, with a P value of 0.007. This means that the more aggressive the disease appeared by standard hematological measures, the more profoundly the circadian clock gene was suppressed. WEE1 expression, in contrast, showed no significant correlation with any of the hematological parameters evaluated, including white blood cell count, hemoglobin, platelet count, and blast percentage.

To understand why these findings matter, it helps to appreciate how deeply the circadian clock and the cell cycle are intertwined. The clock operates through a transcription-translation feedback loop: BMAL1 pairs with CLOCK to activate expression of Period and Cryptochrome genes, whose protein products later feed back to inhibit BMAL1-CLOCK activity, creating an oscillation with a period of roughly 24 hours. Crucially, many of the genes controlled by this loop are involved in cell division. Landmark work published in Science in 2003 showed that the clock directly times cell division in vivo, and subsequent studies demonstrated that BMAL1 regulates the expression of p21, a key inhibitor of cell proliferation. When BMAL1 activity collapses, this timing coordination is lost, and cells may divide without the temporal safeguards that normally restrain them.

WEE1 sits at the intersection of this crosstalk. The kinase phosphorylates and inhibits CDK1, the master driver of mitotic entry, thereby enforcing the G2/M checkpoint that gives cells time to repair DNA damage before dividing. Loss of WEE1 function is known to produce genomic instability, and experiments in mice have shown that WEE1 deficiency leads to hyperactivation of the APC/C complex, chromosomal abnormalities, and ultimately carcinogenesis. At the same time, WEE1 has become a major target in cancer drug development, because many tumors become dependent on WEE1-mediated checkpoint control to survive the DNA damage inflicted by chemotherapy. WEE1 inhibitors are currently being explored in clinical trials across a range of malignancies, and prior work has suggested that WEE1 and PARP-1 play critical roles in the treatment of myelodysplastic syndrome and acute myeloid leukemia.

The downregulation of both genes in pediatric AML therefore paints a coherent, if preliminary, mechanistic picture. A silenced BMAL1 could mean that the leukemic cells have lost clock-driven control of proliferation and DNA damage responses, while reduced WEE1 might reflect a breakdown of checkpoint integrity that allows genetically damaged cells to progress through the cycle. It is worth noting, however, that the relationship between BMAL1 and cancer is not simple. Some studies have found that BMAL1 can actually accelerate certain tumors; one 2023 investigation reported that the clock protein promotes acute myeloid leukemia progression by inhibiting ferroptosis, a form of regulated cell death, through the EBF3/ALOX15 axis. In other cancers, including pancreatic, colorectal, and tongue squamous cell carcinoma, BMAL1 appears to act as a tumor suppressor, and its loss promotes growth and drug resistance. The new pediatric AML data, showing that lower BMAL1 tracks with higher tumor burden, leans toward the tumor-suppressive interpretation in this context, but the authors are careful to frame the finding as suggestive of a role rather than proof of one.

The study also fits into a broader literature on clock gene disruption in blood cancers. Researchers have previously documented downregulation of circadian genes in chronic myeloid leukemia, where altered methylation patterns of the PER3 gene have been observed, and in chronic lymphocytic leukemia, where both clock genes and clock-controlled cell cycle genes show deregulated expression. More recently, the circadian clock circuitry has been shown to modulate the activity of leukemia-initiating cells in T-cell acute lymphoblastic leukemia, and BMAL1 and CLOCK expression patterns have been examined as potential diagnostic markers in multiple myeloma. Animal work adds further weight to the connection: disrupting the light-dark cycle in mice has been shown to impair the hematopoietic function of the bone marrow, the very tissue from which leukemia arises.

For clinicians and researchers, the immediate value of the study lies in its potential biomarker implications. Because BMAL1 expression correlated inversely with white blood cell count and blast percentage, it is conceivable that measuring clock gene activity could eventually help gauge disease burden or track response to therapy in pediatric AML, a disease in which risk stratification remains a major clinical challenge. The authors also point toward therapeutic possibilities, noting that the significant downregulation of BMAL1 and WEE1 suggests that disrupted circadian and cell cycle regulatory pathways may contribute to the pathogenesis of the disease. The emerging field of chronotherapy, which seeks to time drug administration to the patient’s internal rhythms to maximize efficacy and minimize toxicity, could also be informed by a better understanding of how the clock is rewired in leukemic cells.

Significant caveats remain. The study involved a relatively modest sample of 40 patients from a single center, and it measured messenger RNA rather than protein levels, leaving open the question of whether the observed transcriptional changes translate into altered protein function. Correlation does not establish causation, and it is not yet clear whether BMAL1 suppression drives leukemic progression or is merely a consequence of it. The authors note that the data supporting the findings are available from the corresponding author upon reasonable request, and the work was carried out under the ethical oversight of Mashhad University of Medical Sciences with written informed consent from the parents or legal guardians of all pediatric participants. Follow-up studies with larger cohorts, longitudinal sampling, and functional experiments in leukemic cell models will be needed to determine whether restoring clock gene activity could one day form part of a therapeutic strategy. For now, the message is clear and quietly profound: the machinery that tells our cells what time it is may also help decide whether they stay healthy, and in the bone marrow of children with acute myeloid leukemia, that machinery appears to have fallen silent.

Subject of Research: Dysregulation of the circadian clock gene BMAL1 and the cell cycle regulator WEE1 in pediatric acute myeloid leukemia

Article Title: Dysregulation of circadian clock gene BMAL1 and cell cycle regulator WEE1 in pediatric AML

Article References: Oraei Sajjadi, K., Ayatollahi, H., Sheikhi, M., & Ahmadi, M. H. (2026). Dysregulation of circadian clock gene BMAL1 and cell cycle regulator WEE1 in pediatric AML. Molecular Biology Reports, 53(1), Article 1624. https://doi.org/10.1007/s11033-026-12812-9

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12812-9

Keywords: acute myeloid leukemia, BMAL1, WEE1, circadian clock, cell cycle, pediatric cancer, gene expression, bone marrow, G2/M checkpoint, hematologic malignancy, chronotherapy, biomarker