Age-associated transcriptomic heterogeneity in acute myeloid leukaemia: Evidence for mitochondrial metabolic rewiring and suppressed erythroid differentiation in older patients

Abstract

Background: The incidence and clinical aggressiveness of acute myeloid leukaemia (AML) both increase with patient age, yet the transcriptional programmes that distinguish older from younger AML remain incompletely defined. We characterised age-associated gene expression patterns in treatment-naïve adult AML using bone marrow RNA-sequencing data. Methods: Bone marrow RNA-sequencing data from 157 treatment-naïve adult AML patients (18-74 years) in the GSE201492 dataset (Gene Expression Omnibus) were processed to transcripts-per-million (TPM) values and log2-transformed. Age-associated differential expression was assessed using limma, first modelling age as a continuous variable and then comparing patients stratified at a clinically established threshold of 60 years (older, n = 14; younger, n = 143), with sex included as a covariate in both models. Gene Ontology (GO) biological process over-representation analysis was performed on genes significantly altered between age groups. Results: No gene reached significance when age was modelled continuously after Benjamini-Hochberg correction (minimum adjusted P = 0.136). In contrast, the categorical comparison identified 1,890 differentially expressed genes between older and younger patients (adjusted P < 0.05), of which 1,144 were upregulated and 746 were downregulated in older patients. Genes upregulated with age were markedly enriched for mitochondrial respiration, oxidative phosphorylation, and ATP metabolic processes (205 GO terms, adjusted P < 0.05), while downregulated genes were enriched for erythroid development, erythroid differentiation, and myeloid cell homeostasis (15 GO terms), including reduced expression of haemoglobin genes (HBA1, HBA2, HBB, HBD) and the erythroid regulator TAL1. Conclusions: Age-related transcriptomic heterogeneity in AML is dominated by a coordinated upregulation of mitochondrial oxidative metabolism and suppression of erythroid differentiation programmes in patients aged 60 years and older. These findings, generated using a threshold rather than a linear model of age, suggest that age-associated transcriptional change in AML is non-linear and may contribute to the distinct clinical presentation, anaemia burden, and inferior outcomes of older patients, nominating oxidative phosphorylation as a candidate therapeutic vulnerability in this population.