Pan-Cancer Investigation of RFX Family and Associated Genes Identifies RFX8 As a Therapeutic Target in Leukemia

Background Several transcription factors and co-factors are encoded by the RFX (Regulatory Factor X) family (RFX1-8) and associated genes (RFXAP and RFXANK). Increasing evidence suggests that the RFX family and associated genes are involved in the development and progression of cancer. However, no prior research has focused on a multi-omic analysis of these genes to evaluate their role in tumor progression. Methods Using combined TCGA and GTEx pan-cancer data, we investigated the expression patterns and survival profiles of these ten genes. We then focused on RFX8 to analyze its clinicopathological and therapeutic features. Finally, we conducted experimental validation of RFX8 function in acute myeloid leukemia (AML). Results RFX5 and RFXANK showed higher expression levels, while RFX6 showed lower expression levels in most types of cancer, with RFX8 being the most upregulated in LAML. RFX2 and RFXAP demonstrated prognostic significance in eight types of cancer, and RFX8 showed significance in six types of cancer. The expression of these ten genes exhibited specific characteristics in immune subtypes, tumor microenvironment, and stemness. The expression of RFX8 was correlated with various tumor stages, microsatellite instability (MSI), tumor mutation burden (TMB), immune cell infiltration, and immune-checkpoint expression. Additionally, RFX8 was found to regulate tumorigenesis and sensitivity to chelerythrine in AML. Conclusions Our work delineated the landscape of the RFX family and associated genes in the pan-cancer context and the specific role of RFX8 in AML. These findings might offer cues for further investigations of these genes in cancer biology..