Implications of the Chronic Stress Pathway in Acute Myeloid Leukemia

Introduction: Prolonged and repeated exposure to psychological stress triggers various endocrine and behavioral responses. The neuroendocrine system, particularly the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), plays a crucial role in this process. Under chronic stress, the activation of the HPA axis stimulates the adrenal cortex to produce corticosteroids, such as glucocorticoids. Additionally, chronic stress activates the SNS, leading to the secretion of epinephrine. Chronic stress has been linked to the progression and worse outcomes of different types of cancer, but its role in acute myeloid leukemia (AML) is not well defined. To address this gap, we aimed to investigate the influence of the chronic stress pathway on the clinical and molecular features as well as in the outcomes of patients with AML.

Methods: Patients with newly diagnosed AML were retrieved from the publicly available Oregon Health and Science University Beat AML database through cBioPortal for Cancer Genomics. To assess the impact of glucocorticoid and adrenergic pathways on AML, the expression of these hormones' receptors, namely nuclear receptor subfamily 3 group C member 1 (NR3C1) and beta-adrenergic receptor 2 (ADRB2) were considered in tandem as biomarkers for chronic stress. The patients were divided into two groups according to the mean value of both receptors in ADRB2^low/NR3C1^low and ADRB2^high/NR3C1^high. Tumors with high expression of ADRB2 and low expression of NR3C1 or vice-versa were excluded. Differentially expressed genes (DEGs) were identified through differential expression analysis. We queried the Search Tool for the Retrieval of Interacting Genes (STRING) database with the DEGs, log2 ratio, and p values to build a protein-protein interaction network, which was analyzed in the Cytoscape software. Overall survival curves were generated using Kaplan-Meier method and the comparison of the survival rates was performed using log-rank test. Values of p below 0.05 were considered statistically significant.

Results: Among the 409 patients with newly diagnosed AML, 111 were included in the ADRB2^low/NR3C1^low group, 134, in the ADRB2^high/NR3C1^high group, and 164 were excluded from the analysis for not fitting in coincident categories. A preliminary analysis using paired samples of ten patients obtained at diagnosis and at time of relapse showed that the expression of ADRB2 (p=0.047) and NR3C1 (p=0.030) decreased. To investigate whether under chronic stress there might be exhaustion of the receptors, we evaluated the expression of ADRBK2 (responsible for deactivating ADRB2) and HSD11B1L (enzyme that converts cortisol to its active form) and observed that the expression of ADRBK2 (p=0.044) decreased while levels of HSD11B1L (p=0.034) increased in relapsed AML, confirming our hypothesis. Thus, we adopted the joint low expression of ADRB2 and NR3C1 as a biomarker of chronic stress in the subsequent analyses.

More ADRB2^low/NR3C1^low patients presented AML transformed from a previous hematologic malignancy (26.1% vs 7.5%, p<0.001), had prior myelodysplastic syndrome (MDS, 28% vs 2%, p<0.001), higher tumor mutational burden (0.32 vs 0.23, p=0.011), and were classified as adverse risk according to the European LeukemiaNet 2017 classification (ELN, 66.7% vs 44%, p<0.001). There was no statistically significant difference between the groups in terms of sex, race, and ethnicity (p>0.05). Furthermore, more patients under chronic stress (ADRB2^low/NR3C1^low) were refractory to induction treatment (40.8% vs 26.6%, p=0.042). In line with this finding, we identified that the ABCB1 pathway was upregulated in ADRB2^low/NR3C1^low patients. AML patients falling in the ADRB2^low/NR3C1^low category had lower overall survival (p=0.047).

Conclusion: Our findings suggest that chronic stress negatively interferes with the response of AML patients to induction therapy and exerts a critical role in the inferior outcomes of these individuals. We acknowledge the limitation of adopting the expression of ADRB2 and NR3C1 as biomarkers for chronic stress as the clinical evaluation is an important piece of this puzzle. As future perspectives, we suggest the validation of ADRB2 and NR3C1 as chronic stress biomarkers by integrating their expression with the evaluation of patients' mental health and the circulating levels of the stress hormones.

Cortes:Novartis: Consultancy, Research Funding; Lilly: Consultancy; Sun Pharma: Consultancy, Research Funding; Syndax: Consultancy; Rigel: Consultancy; AbbVie: Research Funding; Ascentage: Research Funding; Pfizer: Consultancy; Nerviano: Consultancy; Biopath Holdings: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees.