Abstract
BACKGROUND: Cytogenetically normal acute myeloid leukemia (CN-AML), the most heterogeneous subgroup, requires molecular markers for effective management. Recent studies have highlighted abnormal lipid metabolism as a critical feature driving AML progression, and Sterol Regulatory Element-Binding Factor 2 (SREBF2) - a key regulator of cholesterol metabolism - orchestrates this process by controlling genes involved in sterol biosynthesis and uptake to maintain cellular cholesterol homeostasis. Nevertheless, the prognostic value of SREBF2 in CN-AML remains incompletely understood, necessitating further investigation to clarify its mechanistic role and clinical impact. METHODS: We explored the prognostic implications of SREBF2 expression in two independent large-scale CN-AML patient cohorts. Using integrated multi-omics analysis of transcriptomic data, we characterized the molecular networks and pathways associated with SREBF2. Furthermore, we investigated the microRNA-target interaction network and epigenetic modifications of SREBF2 to unravel its functional role in leukemogenesis. RESULTS: In an independent CN-AML cohort (n = 185), SREBF2 overexpression was significantly associated with adverse overall survival (OS: P = 0.005) and event-free survival (EFS: P = 0.006). Stratified analysis confirmed prognostic significance across subgroups (NCCN Intermediate Risk: OS P = 0.003, EFS P = 0.019; non-M3: OS P = 0.005, EFS P = 0.021). Moreover, multivariable analysis confirmed SREBF2 as an essential unfavorable element in CN-AML patients. Multi-omics analysis revealed SREBF2-associated molecular alterations, including leukemia-related gene co-expression, immune pathway dysregulation, microRNA/DNA methylation changes, and structural variants in the 1st exon/5'UTR region. CONCLUSIONS: Our study identified SREBF2 as a novel prognostic biomarker in CN-AML. Through gene enrichment and microRNA network analysis, SREBF2 interactions with genomic/transcriptomic elements were found to drive CN-AML pathogenesis, providing clinical insights for treatment strategies.