What question did this study set out to answer?

To explore how FOXN3 influences E2F5 expression and its implications in acute myeloid leukemia.

March 26, 2026Open Access

Crosstalk Between FOXN3 and E2F5 Reveals a Novel Tumor Suppressive Pathway in Acute Myeloid Leukemia via MAPK Signaling: Implications for Potential Future Targeted Therapy

Puntos clave

To explore how FOXN3 influences E2F5 expression and its implications in acute myeloid leukemia.
Conducted ChIP-seq to identify FOXN3 target genes in AML.
Performed bioinformatics analyses for pathway enrichment relating to cell cycle and apoptosis.
Validated gene regulation using RT-qPCR, Western blotting, and luciferase reporter assays.
Executed functional studies with FOXN3 knockdown and overexpression in AML cells.
Investigated interaction between FOXN3 and E2F5 through co-transfection with lentiviruses.
FOXN3 overexpression decreased E2F5 mRNA and protein levels.
E2F5 was found to be elevated in AML, correlating with poor prognosis.
Functional studies indicated E2F5 promotes cell proliferation and inhibits apoptosis in AML.
Co-transfection of E2F5 counteracted the inhibitory effects of FOXN3 on cell proliferation.
FOXN3 modulates MAPK signaling pathway, affecting downstream target EZH2.

Resumen

Objective: To investigate the mechanism of FOXN3 in acute leukemia. Methods: ChIP-seq experiments were performed using FOXN3-specific antibodies to identify FOXN3 target genes in acute myeloid leukemia (AML). Bioinformatics analyses were conducted to determine the enrichment of biological processes and pathways related to cell cycle regulation and apoptosis among the target genes. The transcriptional regulation of the gene of interest was confirmed through RT-qPCR, Western blotting, and luciferase reporter assays. Additionally, we examined the significance of FOXN3 on the prognosis of AML patients. Functional studies were performed following the knockdown and overexpression of the target gene in AML cells. Furthermore, we investigated the interaction between FOXN3 and the target gene by co-transfecting AML cells with lentiviruses overexpressing the target gene, followed by examinations of downstream signaling pathways through RNA-seq and pathway enrichment analyses. Results: FOXN3 regulates E2F5 expression, leading to decreased mRNA and protein levels of E2F5 upon FOXN3 overexpression, though additional factors may contribute to this repression. Notably, E2F5 expression was elevated in AML patients and cell lines, correlating with unfavorable clinical outcomes. Functional investigations revealed that E2F5 functions as an oncogene in AML, promoting cell proliferation, inhibiting apoptosis, and influencing cell cycle progression. Co-transfection experiments demonstrated that E2F5 could counteract the proliferation-inhibitory effect of FOXN3. Additionally, FOXN3 was found to modulate the MAPK signaling pathway and its downstream target, EZH2. Conclusion: This study reveals a novel regulatory axis involving FOXN3 and E2F5 in AML. FOXN3 acts as a tumor suppressor by regulating E2F5 and modulating downstream MAPK signaling pathways. Keywords: forkhead box N3, E2F5, acute myeloid leukemia, mechanism, MAPK, sequencing, survival

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