ACTR5 as a potential therapeutic target in AML: Preliminary mechanistic insights from integrated multi-omics analysis

Actin-Related Protein 5(ACTR5) is essential for tumor progression in hepatocellular carcinoma(HCC), however, its function in acute myeloid leukemia(AML) remains elusive. We aim to characterize the role of ACTR5 in AML progression as well as its potential mechanism. The patient samples from TCGA and GTEx database were utilized to reveal the survival of ACTR5 high-expression(ACTR5^hi) and low-expression(ACTR5^low) through GEPIA online tool. ACTR5 knockout (ACTR5-KO) cell lines were generated by CRISPR/Cas9 gene editing technology and ACTR5 overexpression(ACTR5-OE) cell line was obtained by plenti-CMV transfection system, to assess its impact on cell growth, apoptosis and cell cycle in vitro. Functionally essential targets were revealed via integrative analysis of multi-omics data, including RNA-seq and ATAC-seq, between wild-type and ACTR5-KO cell lines. The ACTR5^hi patients showed a shorter overall survival compared to the ACTR5^low patients in AML group. Besides, ACTR5 depletion inhibited proliferation, promoted apoptosis, and impaired cell cycle progression. Mechanistic studies unveiled ACTR5 as a regulator of cell cycle, including abnormal expression of checkpoints promoting G1/S phase transition(CCND2)and inhibiting S/G2 phase transition(FOS, JUNB). In addition, the functionally essential genes of DNA repair were revealed including the upregulation of RAD50, ATM, CDC20, CDC25C, TERT. Our findings highlight the potential oncogenic role of ACTR5 in poor prognosis, as well as suggesting a potential role for ACTR5 in AML pathogenesis through its association with disrupted cell cycle and DNA repair gene programs.