Dataset Information

Novel tumor-suppressor FOXN3 is downregulated in adult acute myeloid leukemia.

ABSTRACT: Forkhead box protein N3 (FOXN3) is a transcriptional repressor involved in cell cycle regulation and tumorigenesis. Abnormalities in gene structure and epigenetics of FOXN3 are closely associated with the occurrence of hematological malignancies; however, its involvement in the pathogenesis of acute myeloid leukemia (AML) remains unknown. The present study aimed to examine the potential significance of FOXN3 in AML. FOXN3 expression levels were examined in patients with AML and AML cell lines, and its clinical significance in AML was evaluated. FOXN3-overexpressing AML cell lines were established, and the biological function of FOXN3 was detected by flow cytometry and a Cell Counting Kit-8 assay. A significant decrease in FOXN3 expression levels was observed in patients with AML and in the AML cell lines in vitro. FOXN3 expression levels were associated with the number of leukocytes in patients. FOXN3 overexpression may inhibit cell proliferation in AML cell lines, induce cell cycle S-phase arrest and promote apoptosis in OCI-AML3 and THP-AML cells. The present study provided insight into how FOXN3 may serve as a novel tumor suppressor in AML.

SUBMITTER: He H

PROVIDER: S-EPMC6607153 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Novel tumor-suppressor FOXN3 is downregulated in adult acute myeloid leukemia.

He Hang H Zhang Jinjing J Qu Yi Y Wang Yue Y Zhang Yan Y Yan Xiaojing X Li Yan Y Zhang Rui R

Oncology letters 20190531 2

Forkhead box protein N3 (FOXN3) is a transcriptional repressor involved in cell cycle regulation and tumorigenesis. Abnormalities in gene structure and epigenetics of FOXN3 are closely associated with the occurrence of hematological malignancies; however, its involvement in the pathogenesis of acute myeloid leukemia (AML) remains unknown. The present study aimed to examine the potential significance of FOXN3 in AML. FOXN3 expression levels were examined in patients with AML and AML cell lines, a ...[more]

PMID: 31423219

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Project description:BackgroundDysregulation of miRNAs that can act as tumor suppressors or oncogenes can result in tumorigenesis. Previously we demonstrated that miR-199b was significantly downregulated in acute myeloid leukemia (AML) and targets podocalyxin and discoidin domain receptor 1. Herein we investigated the functional role of miR-199b in AML and its prognostic implications.MethodsMajor approaches include transduction of hematopoietic stem cells and bone marrow transplantation, analyses of blood lineages, histone deacetylases (HDAC) inhibitors, and molecular and clinical data analyses of AML patients using The Cancer Genome Atlas (TCGA).ResultsWe first examined the relative miR-199b expression in steady state hematopoiesis and showed CD33(+) myeloid progenitors had the highest miR-199b expression. Further, silencing of miR-199b in CD34(+) cells resulted in significant increases in CFU-GM colonies. Via TCGA we analyzed the molecular and clinical characteristics of 166 AML cases to investigate a prognostic role for miR-199b. The Kaplan-Meier curves for high and low expression values of miR-199b and the observed distribution of miRNA expression revealed the highly expressed group had significantly better survival outcomes (p < 0.016, log rank test). Additionally, there was significant difference between miR-199b expression across the AML subtypes with particularly low expression found in the FAB-M5 subtype. Furthermore, FAB-M5 subtype showed a poor prognosis with a 1-year survival rate of only 25 %, compared with 51 % survival in the overall sample (p < 0.024). Furthermore, significant inverse correlation of HoxA7 and HoxB6 expression with miR-199b was observed in FAB-M5 AML patients. Molecular mutations were analyzed among miR-199b high and low AML cases. Significant correlations in terms of association and survival outcomes were observed for NPMc and IDH1 mutations. Treatment of THP-1 cells (represents M5-subtype) with HDAC inhibitors AR-42, Panobinostat, or Decitabine showed miR-199b expression was significantly elevated upon AR-42 and Panobinostat treatment. To further understand the hematopathological consequences of decreased miR-199b, we employed a bone-marrow transduce/transplant (BMT) mouse model. Interestingly, in vivo miR-199b silencing per-se in HSCs did not result in profound perturbations.ConclusionsLoss of miR-199b can lead to myeloproliferation while HDAC inhibitors restore miR-199b expression and promote apoptosis. Low miR-199b in AML patients correlates with worse overall survival and has prognostic significance for FAB-M5 subtype.

Dataset Information

Novel tumor-suppressor FOXN3 is downregulated in adult acute myeloid leukemia.

Publications

Novel tumor-suppressor FOXN3 is downregulated in adult acute myeloid leukemia.

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