INTERACTION OF ELF-4 AND NPM1 IN AML

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Abstract

ELF-4 is a transcription factor belonging to the ETS family, which is expressed in a wide variety of tissues including hematopoietic cells. It is reported that ELF-4 is essential for the development of NK/NKT cells, regulation of the cell cycle of hematopoietic stem cells, and was shown to be a transcriptional activator whose targets include cytokine genes, such as IL-3, GM-CSF, and IL-8. In this study, we aimed to test the role of ELF-4 in acute myeloid leukemia (AML), especially AML with normal karyotype. Tandem affinity purification assay revealed that nucleophosmin (NPM1) is one of the associated proteins with ELF-4, and that was confirmed using artificially expressed ELF-4 and NPM1 proteins. Co-expression of NPM1 reduced the activity of ELF-4, whereas mutation of NPM1 that is present in about 50% of AML with normal karyotype, increased the transcriptional activity of ELF-4. Along with the transcriptional activity, co-expression of wild type NPM1 decreased, and mutated NPM1 accelerated the transformation of NIH3T3 cells by the over expression of ELF-4. Although mutated NPM1 changes intracellular localization, from nucleus to cytoplasm, its mutation did not affect the localization of ELF-4. Results of the EMSA assay suggested that wild type NPM1 hampers the DNA binding of ELF-4. Since one of the targets of elf-4 is mdm2, a negative regulator of p53, we tested whether ELF-4 regulates the expression of HDM2, human version of mdm2. ChIP assay and luciferase assay using the promoter of HDM2 showed that ELF-4 binds to the one of the putative binding sites, and it transactivates the HDM2 promoter. Co-expression of wild type NPM1 reduced, and mutated NPM1 enhanced the binding of ELF-4 to its promoter.

These results suggested that ELF-4 has an important role in the biology of AML, with a strong relationship with the mutational situation of the NPM1 gene.

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