〔Abstract〕 Objective To investigate the effects of C-type lectin domain family 5,member A(CLEC5A)on the proliferation, apoptosis, and cell cycle of leukemia cell lines THP-1 and K562,and the underlying mechanism. Methods The expression ofCLEC5Ain leukemia patients was investigated in the GEPIA database.Recombined plasmid containingCLEC5Awas transfected into THP-1 and K562 cells for overexpression ofCLEC5A.Small interfering RNA(siRNA)was used to knock down the endogenousCLEC5Ain leukemia cells.CCK-8 and EdU assays were used to assess the leukemia cells proliferation.Flow cytometry was used to assess cell cycle.Flow cytometry was used to assess cell apoptosis under hydrogen peroxide(H2O2)stress.The RNA sequencing(RNA-seq)and pathway enrichment analysis were used to analyze the signal pathways of significant enrichment of up-regulated or down-regulated genes after knocking downCLEC5Agene.Protein expression levels of several members in AKT1/mTOR and p53 signaling pathways were detected by Western blot assays. Results CLEC5Awas significantly up-regulated in bone marrow tissues of leukemia patients compared to the matched non-tumor tissues of healthy individuals.Knockdown ofCLEC5Asignificantly reduced the proliferation(allP<0.01) and S phase progression(allP<0.05),and increased the apoptosis(allP<0.001) under H2O2stress, in THP-1 and K562 cells.Conversely, overexpression ofCLEC5Asignificantly increased the proliferation(allP<0.001) and S phase progression(allP<0.01),and reduced the apoptosis(allP<0.01) under H2O2stress, in THP-1 and K562 cells.The up-regulated genes were significantly enriched in AKT1-mTOR and other signal pathways after knocking downCLEC5A,while the down-regulated genes were significantly enriched in cell cycle signal pathways.CLEC5Ain leukemia cells significantly reduced the genes expression levels of BAX and p53,and significantly induced the gene expression levels of BCL-2 and phosphorylation levels of AKT1 and mTOR proteins. Conclusion CLEC5Aincreases the cell cycle and proliferation and inhibits cells apoptosis in THP-1 and K562 cells, and the mechanism may be related to activating the AKT/mTOR and p53 signaling pathways.