Avaliação da expressão dos genes do ritmo circadiano como potenciais biomarcadores em pacientes portadores de leucemia mielóide aguda

Abstract

Acute myeloid leukemia (LMA) is an aggressive hematological malignancy, common in adults, characterized by high mortality and marked genetic heterogeneity. Growing evidence indicates that dysregulation of the circadian rhythm (RC) and its core genes, the Clock Genes (CG), CLOCK, BMAL1, NPAS2, and the negative regulator CIPC, interferes with key oncogenic processes, including cell proliferation, DNA repair, and energy metabolism. In this context, this study aims to evaluate the expression of CG as potential biomarkers in adults with LMA in the state of Ceará. This is a prospective, observational, and analytical study including 90 patients with LMA (mean age 56.6 years; predominantly male) treated at referral centers in Ceará, and 40 healthy controls. Paired peripheral blood (SP) and bone marrow (MO) samples were collected for RNA extraction, cDNA synthesis, and gene expression quantification by RT-qPCR. Diagnostic performance was assessed using ROC curves, logistic regression models, and a Random Forest algorithm. No significant differences were observed in CG expression between SP and MO, supporting the use of SP as a surrogate tissue. Patients with LMA showed a marked reduction in the expression of NPAS2, BMAL1, CLOCK, and CIPC compared to controls (p<0.001). Among individual markers, NPAS2 demonstrated the best discriminative performance (AUC 0.925; 95% CI: 0.87–0.98), explaining 65.1% of the outcome variability in the logistic model. The combined four-gene model achieved an AUC of 0.946, with no statistically significant improvement over the model with NPAS2 alone (p=0.183). The Random Forest model showed 74% sensitivity and 100% specificity, highlighting NPAS2 as the most important predictive variable. Thus, LMA is associated with a marked dysregulation of CG expression. NPAS2 stands out as a robust diagnostic biomarker, with high discriminative performance and potential clinical applicability. These findings expand the understanding of leukemogenesis from a circadian perspective and support the exploration of biological clock pathways as diagnostic and therapeutic targets.