Molecular mechanisms of circadian clock-mediated gene regulation and their implications in leukemia.

Leukemia progression is driven by complex molecular alterations that disrupt both intracellular signaling and circadian regulation. The circadian clock, composed of core regulators such as CLOCK, BMAL1, PER1–3, CRY1–2, REV-ERBs, and RORs, orchestrates cellular proliferation, apoptosis, and metabolism in alignment with the 24-h cycle. Emerging evidence indicates that circadian components intricately interact with major oncogenic pathways—including PI3K/AKT/mTOR, MAPK, JAK/STAT, Notch, Wnt/β-catenin, FOXO, and NF-κB—that govern hematopoietic function and leukemogenesis. Disruption of circadian timing perturbs these pathways, leading to excessive proliferation, metabolic imbalance, inflammation, and therapeutic resistance. Notably, REV-ERBα suppresses JAK/STAT3 signaling via SOCS3 induction, while AKT-mediated phosphorylation of BMAL1 and CLOCK alters their activity and localization. Moreover, circadian modulation of MAPK, mTOR, Notch, and Wnt pathways regulates stem cell renewal and differentiation, implicating clock dysfunction in malignant transformation. Downregulation of core clock genes, including CLOCK, BMAL1, REV-ERBα, PPARα, and PER1–3, has been reported across multiple leukemia subtypes, underscoring their tumor-suppressive roles. This review highlights the molecular crosstalk between circadian regulators and oncogenic signaling in leukemia, emphasizing their collective influence on disease progression and the potential of chronotherapeutic approaches to enhance treatment outcomes.