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miR-454-3p is considered to have a crucial role in cancer progression, but the potential involvement in acute myeloid leukemia (AML) remains unclear. Expression of miR-454-3p and ZEB2 mRNA and protein were quantified in AML cell lines. Cells were transfected with miR-454-3p inhibitor or mimic and cell growth was assessed by colony formation and CCK-8 assays and the cell cycle, apoptosis and autophagy were investigated by Western blotting, flow cytometry, immunofluorescence and 3-methyladenine (3-MA) treatment. miR-454-3p expression was attenuated in AML cells. miR-454-3p overexpression attenuated cell growth and stimulated cell cycle arrest, apoptosis and autophagy. Dual-luciferase reporter assays and bioinformatics analysis showed that AML progression was inhibited when miR-454-3p regulated ZEB2, an effect confirmed by rescue assays. 3-MA reduced the autophagy-inducing effect of ZEB2 knockdown and indicated that autophagy induced apoptosis. miR-454-3p downregulated p-mTOR/p-AKT levels in AML cells. The novel role of miR-454-3p as a tumor inhibitor in AML via regulation of the ZEB2/AKT/mTOR axis was demonstrated, indicating miR-454-3p as a potential new molecular target for AML. [ABSTRACT FROM AUTHOR]

Background: DNA methyltransferase 3A (DNMT3A) often mutate on arginine 882 (DNMT3AR882) in acute myeloid leukemia (AML). AML patients with DNMT3A R882 mutation are usually resistant to daunorubicin treatment; however, the associated mechanism is still unclear. Therefore, it is urgent to investigate daunorubicin resistance in AML patients with DNMT3A R882 mutant. Method: AML cell lines with DNMT3A-wild type (DNMT3A-WT), and DNMT3A-Arg882His (DNMT3A-R882H) mutation were constructed to investigate the role of DNMT3A R882H mutation on cell proliferation, apoptosis and cells' sensitivity to Danunorubin. Bioinformatics was used to analyze the role of nuclear factor-E2-related factor (NRF2) in AML patients with DNMT3A R882 mutation. The regulatory mechanism of DNMT3A R882H mutation on NRF2 was studied by Bisulfite Sequencing and CO-IP. NRF2 inhibitor Brusatol (Bru) was used to explore the role of NRF2 in AML cells carried DNMT3A R882H mutation. Results: AML cells with a DNMT3A R882H mutation showed high proliferative and anti-apoptotic activities. In addition, mutant cells were less sensitive to daunorubicin and had a higher NRF2 expression compared with those in WT cells. Furthermore, the NRF2/NQO1 pathway was activated in mutant cells in response to daunorubicin treatment. DNMT3A R882H mutation regulated the expression of NRF2 via influencing protein stability rather than decreasing methylation of NRF2 promoter. Also, NRF2/NQO1 pathway inhibition improved mutant cells' sensitivity to daunorubicin significantly. Conclusion: Our findings identified NRF2 as an important player in the regulation of cell apoptosis through which helps mediate chemoresistance to daunorubicin in AML cells with DNMT3A R882H mutation. Targeting NRF2 might be a novel therapeutic approach to treat AML patients with a DNMT3A R882H mutation. 9jD1n7ooVY8uHe1s9Su8KL Video abstract [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA)-222-3p is overexpressed in numerous tumors, where it acts as an oncogene. Although miRNA-222 is highly expressed in acute myeloid leukemia (AML), its functions and the mechanisms underlying these functions have not yet been fully elucidated. This study aimed to investigate the regulatory roles of miRNA-222-3p in AML and the molecular mechanisms underlying these roles. In this study, we observed that miRNA-222-3p increased the viability and suppressed the apoptosis of AML cells. Axin2 was demonstrated to be a direct target of miRNA-222-3p, which when overexpressed, inhibited Axin2 expression and stimulated the Wnt/β-catenin pathway. In contrast, upregulation of Axin2 expression levels reduced the viability and enhanced the apoptosis of AML cells. Moreover, it partially reversed the effects of the miRNA-222-3p mimic on the proliferation and apoptosis of, and modulation of the Wnt/β-catenin pathway in, AML cells. Taken together, this study provides strong evidence that miRNA-222-3p can serve as a molecular target for AML treatment. • miRNA-222-3p is upregulated in AML cells. • miRNA-222-3p enhances the proliferation and suppresses the apoptosis in AML cells by directly targeting Axin2. • Axin2 upregulation inhibits the proliferation and accelerates the apoptosis in AML cells. • miRNA-222-3p amplifies the Wnt/β-catenin signaling pathway in AML cells via targeting Axin2. [ABSTRACT FROM AUTHOR]

Studies have confirmed that acute myeloid leukemia (AML) cells with DNA methyltransferase 3A Arg882His (DNMT3A R882H) mutation show an increased proliferation capability. However, the associated mechanism is still unclear. Glycolysis is involved in regulating malignant proliferation of cancer cell. Hence, we analyzed whether the DNMT3A R882H mutation interferes with glycolysis and thereby influences AML cell proliferation. We generated AML cell line carrying a DNMT3A-R882H mutation and compared it with the wild type (DNMT3A-WT) with regard to glycolysis regulation. Moreover, we analyzed the cell line's proliferation and apoptosis by a CCK-8 assay, western blotting, and flow cytometry. The role of NRF2/NQO1 signaling in regulating glycolysis was investigated by NRF2-knockdown and Brusatol (specific inhibitor of NRF2) treatment. DNMT3A R882H cells had a higher glucose transport capacity compared to WT cells and their viability could be reduced by glucose deprivation. Moreover, daunorubicin had a slight inhibitory effect on glycolysis while glycolysis inhibition re-sensitized mutant cells to daunorubicin. Obviously, DNMT3A R882H mutation activated the NRF2/NQO1 pathway and enhanced the glycolytic activity in mutant cells. Taken together, these results suggest a novel mechanism by which a DNMT3A R882H mutation promotes glycolysis via activation of NRF2/NQO1 pathway. A parallel glycolysis inhibition adds to the anticancer effects of daunorubicin which might lead to a novel therapeutic approach for the treatment of AML patients carrying a DNMT3A R882H mutation. • Glycolytic activity was enhanced in AML cells with DNMT3A R882H mutation. • The survival of DNMT3A R882H mutant cells depended on glycolysis. • DNMT3A R882H mutation promotes AML cell proliferation via regulating NRF2/NQO1/glycolysis pathway. • DNMT3A R882H mutation reduces the inhibitory role of Daunorubicin on glycolysis. • NRF2 inhibition enhances the role of Daunorubicin on impeding glycolytic activity. [ABSTRACT FROM AUTHOR]

Polo-like kinase 4 (PLK4) is a crucial regulator for centriole replication and is reported to be aberrantly expressed in various cancers, where it participates to tumorigenesis. However, PLK4 effect in acute myeloid leukemia (AML), is still uncertain. This study investigates the function of PLK4 in AML. Quantitative real-time PCR was used to measure the level of PLK4. Centrinone, a selective PLK4 small molecule inhibitor, was used for PLK4 inhibition and explore its effect in AML cells. The cell growth was detected by the CCK8, while the cell cycle and apoptosis were assessed by flow cytometry. The level of proteins associated with apoptosis, cell cycle and endoplasmic reticulum (ER) stress were analyzed by western blotting. PLK4 was overexpressed in AML cells. PLK4 knockdown or its specific inhibition by centrinone induced G2/M phase arrest via suppressing the expression of cyclin B1 and Cdc2 and promoting the level of proapoptotic proteins. Moreover, PLK4 targeting enhanced the level of proteins related to ER stress, such as GRP78, ATF4, ATF6, and CHOP. These findings demonstrated that targeting PLK4 can induce apoptosis, G2/M and ER stress in AML cells. [ABSTRACT FROM AUTHOR]

MiRNA-301b-3p functions as an oncomiRNA or tumor suppressor, and has been reported in various cancer types, including pancreatic, colorectal, oral, hepatocellular and lung cancers. Although the expression of miRNA-301b-3p is upregulated in acute myeloid leukemia (AML), its biological function and precise mechanisms remain unclarified. This study explores the roles of miRNA-301b-3p in AML, with the aim of ascertaining its regulatory action on Wnt/β-catenin axis by targeting Forkhead box F2 (FOXF2). The expression levels of miRNA-301b-3p and FOXF2 were measured by quantitative real-time PCR. The effects of miRNA-301b-3p knockdown and overexpression on cell proliferation were evaluated by CCK8 and cell counting assays, while cell apoptosis was analyzed by flow cytometry. The expression levels of apoptosis-related proteins, including FOXF2, and other targets in Wnt/β-catenin axis were determined by immunoblotting. Possible interaction between miRNA-301-3p and FOXF2 in AML cells was examined by luciferase reporter assays. MiRNA-301b-3p was dramatically upregulated in AML cells, and showed a negative correlation with FOXF2 expression. Downregulation of miRNA-301b-3p suppressed proliferation and promoted apoptosis in AML cells. MiRNA-301b targeted FOXF2 to regulate Wnt/β-catenin axis. In the rescue experiments, FOXF2 overexpression partly reversed the effect of miRNA-301b-3p mimic in AML cells. The current findings demonstrate that miRNA-301b-3p targets FOXF2 to induce proliferation and inhibit apoptosis in AML cells via regulation of Wnt/β-catenin axis. • MiR-301b-3p is frequently upregulated in AML, and miR-301b-3p overexpression facilitates the cell proliferation of AML cells. • MiR-301b-3p is involved in the progression of AML by directly targeting FOXF2. • MiR-301b-3p promotes the activation of Wnt/β-catenin signaling in AML through a direct targeting of FOXF2. [ABSTRACT FROM AUTHOR]