Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the uncontrolled proliferation of immature myeloid cells in the bone marrow, impairing normal hematopoiesis. Although conventional chemotherapy remains the standard treatment, particularly in patients under 60 years of age, overall survival remains limited, mainly due to high relapse rates. One of the mechanisms implicated in disease progression is immune evasion, driven by the overexpression of inhibitory receptors, such as PD-1 and TIM-3, on T cells, leading to an exhausted phenotype characterized by impaired proliferation, cytokine production, and cytotoxic activity. Additionally, the tumor microenvironment contributes to this scenario by expressing high levels of ligands such as PD-L1, thereby promoting disease progression.

This study aimed to: (i) evaluate the expression of the PDCD1 (PD-1) and HAVCR2 (TIM-3) genes in AML patients; (ii) correlate gene expression levels with overall survival; and (iii) analyze the promoter methylation profiles of these genes across different age groups.

Public data from the TCGA were analyzed using the GEPIA2 and UALCAN platforms. PDCD1 and HAVCR2 expression was compared between 173 AML patients and 70 control individuals. Overall survival was assessed using Kaplan-Meier curves, stratifying patients into high- and low-expression groups (n = 53 per group), with the log-rank test applied (p < 0.05; 95% CI).

Promoter methylation was evaluated in 193 AML samples, stratified by age. Expression levels of PDCD1 and HAVCR2 were significantly higher in AML patients compared to controls (p < 0.001). Overexpression of these genes was associated with reduced overall survival (p = 0.0017) and a 2.4-fold increased hazard ratio (p = 0.0022). Patients aged 21–40 years showed promoter hypermethylation of PDCD1 (β = 0.72) compared to the 61–80 (p = 0.00290) and 81–100 age groups (p = 0.00292). For HAVCR2, hypomethylation was observed in individuals aged 41–60 years (β = 0.34) compared to the 61–80 group (p = 0.0062).

These findings underscore the central role of immune exhaustion in AML pathophysiology, highlighting the overexpression of PDCD1 and HAVCR2 as contributors to a tumor-permissive microenvironment and worse prognosis. The epigenetic analysis suggests age-related regulation of these genes, with PDCD1 hypermethylation in younger patients—possibly indicating active transcriptional repression—and loss of this regulation in older individuals. The HAVCR2 hypomethylation observed in middle-aged patients may explain its increased expression and the intensification of the T cell exhaustion phenotype in this group.The overexpression of PDCD1 and HAVCR2 is associated with immune exhaustion, reduced survival, and probable epigenetic dysregulation in AML patients. These findings reinforce their potential as prognostic biomarkers and highlight the relevance of exploring epigenetically modulated immunotherapeutic targets in AML.