ARF6 Promotes AML Progression via Activation of PI3K/AKT/mTOR Signaling

Acute myeloid leukemia (AML) represents a highly aggressive hematological malignancy characterized by a poor prognosis and a pressing demand for innovative diagnostic and prognostic biomarkers. Recent studies have indicated that ADP-ribosylation factor 6 (ARF6) is overexpressed across various cancer types; however, its specific role and implications in AML have yet to be thoroughly investigated.

To elucidate the clinical relevance and functional mechanisms of ARF6 in AML, we conducted an integrated analysis utilizing RNA sequencing data from The Cancer Genome Atlas (TCGA) alongside clinical samples and AML cell lines. The diagnostic potential of ARF6 was assessed through receiver operating characteristic curve analysis, and logistic regression was employed to identify factors correlating with elevated ARF6 expression. Functional assays were performed to elucidate the effects of ARF6 modulation on apoptosis, cell cycle progression, and AML cell proliferation, while mechanistic investigations focused on the PI3K/AKT/mTOR signaling pathway, particularly in the context of pharmacological PI3K inhibition.

Our findings revealed a significant upregulation of ARF6 in AML compared to normal controls, with diagnostic efficacy indicated by an AUC of 0.793. Logistic regression analysis identified older age (> 60 years) and a higher white blood cell count (> 20 × 10⁹/L) as significant predictors of high ARF6 expression. Moreover, elevated ARF6 levels were independently associated with shorter overall survival (HR = 1.634, p = 0.045). Notably, ARF6 knockdown induced apoptosis and G0/G1 cell cycle arrest, whereas its overexpression yielded contrary effects. In addition, ARF6 activated the PI3K/AKT/mTOR pathway, which was abrogated by pharmacological PI3K inhibition.

Collectively, our findings establish ARF6 as a valuable diagnostic and prognostic marker in AML, driving disease progression through the activation of the PI3K/AKT/mTOR pathway. These insights not only enhance our understanding of AML pathology but also underscore the potential of targeting ARF6 for therapeutic intervention in AML treatment paradigms. Future research should aim at evaluating the therapeutic implications of targeting ARF6 in combination with existing treatment modalities.