MYCN Contributes to the Sensitization of Acute Myelogenous Leukemia Cells to Cisplatin by Targeting SRY-box Transcription Factor 4.

Little was known about the role of MYCN in drug resistance in acute myeloid leukemia (AML). We investigated impacts of MYCN on sensitization of AML cell to cisplatin, and its interaction with SRY-box transcription factor 4 (SOX4). In vitro, human AML cell lines HL60 and KG-1 were transfected with the overexpression plasmids and specific small interfering RNA of MYCN (siMYCN), or siSOX4, and then treated with 2 μg/mL cisplatin. MTT and flow cytometry assays were performed to estimate the viability and apoptosis of AML cell. The expressions of MYCN and SOX4 in AML patients and the associations between these two were analyzed by bioinformatics analysis, luciferase assay and quantitative reverse transcription polymerase chain reaction (qRT-PCR). In vivo, transfected HL60 cells were injected into BALB/c nude mice. The tumor size and weight were recorded, and the expressions of MYCN and SOX4 were determined with immunohistochemistry. MYCY and SOX4 were highly-expressed in AML, and their expressions were positively correlated. In AML cells, the treatment using cisplatin induced higher MYCN expression and augmented apoptosis, whereas decreasing the viability. Silencing of MYCN enhanced the tumor-suppressive effects of cisplatin on AML by decreasing cell viability and increasing apoptosis. The promoter of SOX4 was targeted by MYCN. Lower cell viability and higher apoptosis rate were seen in AML cells transfected with siSOX4, the effects of which were partially reversed by overexpressed MYCN. Silencing of MYCN retarded the tumor growth and SOX4 expression in tumor in vivo. Collectively, MYCN sensitized AML cells to cisplatin by targeting SOX4.