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Circular RNA ATAD1 is upregulated in acute myeloid leukemia and promotes cancer cell proliferation by downregulating miR-34b via promoter methylation.

ABSTRACT: A previous study has reported the oncogenic role of circular RNA (circ)-ATAD1 in gastric cancer. The aim of the present study was to investigate the role of circ-ATAD1 in acute myeloid leukemia (AML). Bone marrow mononuclear cells were collected from 60 patients with AML and 60 healthy controls, followed by RNA isolation and reverse transcription-quantitative PCR to assess the expression of circ-ATAD1 and microRNA (miR)-34b. A subcellular fractionation assay was used to determine the subcellular location of circ-ATAD1 in AML cells. Furthermore, circ-ATAD1 and miR-34b were overexpressed in AML cells to study crosstalk between the two molecules. The effect of circ-ATAD1 overexpression on miR-34b gene methylation was also analyzed by methylation-specific PCR, and the roles of circ-ATAD1 and miR-34b in the regulation of AML cell proliferation were analyzed by BrdU assay. circ-ATAD1 expression was found to be elevated, and inversely correlated with that of miR-34b, in patients with AML. Subcellular fractionation assays showed that circ-ATAD1 was specifically expressed in the nucleus. In addition, circ-ATAD1 overexpression in AML cells decreased miR-34b expression and increased miR-34b gene methylation. Moreover, AML cell proliferation was increased by circ-ATAD1 overexpression, but decreased by miR-34b overexpression, and the effect of circ-ATAD1 overexpression on AML cell proliferation was reduced by miR-34b overexpression. Together, these results indicate circ-ATAD1 as a nucleus-specific circRNA in AML, which promotes AML cell proliferation by downregulating miR-34b via methylation.

SUBMITTER: Wu Y

PROVIDER: S-EPMC8477150 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:MicroRNA-34b down-regulation in acute myeloid leukemia was previously shown to induce CREB overexpression, thereby causing leukemia proliferation in vitro and in vivo. The role of microRNA-34b and CREB in patients with myeloid malignancies has never been evaluated. We examined microRNA-34b expression and the methylation status of its promoter in cells from patients diagnosed with myeloid malignancies. We used gene expression profiling to identify signatures of myeloid transformation. We established that microRNA-34b has suppressor ability and that CREB has oncogenic potential in primary bone marrow cell cultures and in vivo. MicroRNA-34b was found to be up-regulated in pediatric patients with juvenile myelomonocytic leukemia (n=17) and myelodysplastic syndromes (n=28), but was down-regulated in acute myeloid leukemia patients at diagnosis (n=112). Our results showed that hypermethylation of the microRNA-34b promoter occurred in 66% of cases of acute myeloid leukemia explaining the low microRNA-34b levels and CREB overexpression, whereas preleukemic myelodysplastic syndromes and juvenile myelomonocytic leukemia were not associated with hypermethylation or CREB overexpression. In paired samples taken from the same patients when they had myelodysplastic syndrome and again during the subsequent acute myeloid leukemia, we confirmed microRNA-34b promoter hypermethylation at leukemia onset, with 103 CREB target genes differentially expressed between the two disease stages. This subset of CREB targets was confirmed to associate with high-risk myelodysplastic syndromes in a separate cohort of patients (n=20). Seventy-eight of these 103 CREB targets were also differentially expressed between healthy samples (n=11) and de novo acute myeloid leukemia (n=72). Further, low microRNA-34b and high CREB expression levels induced aberrant myelopoiesis through CREB-dependent pathways in vitro and in vivo. In conclusion, we suggest that microRNA-34b controls CREB expression and contributes to myeloid transformation from both healthy bone marrow and myelodysplastic syndromes. We identified a subset of CREB target genes that represents a novel transcriptional network that may control myeloid transformation.

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Circular RNA ATAD1 is upregulated in acute myeloid leukemia and promotes cancer cell proliferation by downregulating miR-34b via promoter methylation.

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