On the role of the fusion protein DEK-NUP214 in leukemogenesis

Sammanfattning: The t(6;9) translocation is found in a subset of patients with acute myeloid leukemia (AML) and is associated with a poor prognosis. The translocation results in the formation of the DEK-NUP214 fusion protein containing almost the entire nuclear protein DEK and two thirds of the nucleoporin NUP214. The molecular mechanisms behind the leukemic conversion of cells expressing the fusion protein DEK-NUP214 have not yet been elucidated. We have identified that cells expressing DEK-NUP214 show increased protein synthesis and proproliferative effects of DEK and DEK-NUP214 have been discovered. In addition, the effect of DEK-NUP214 is independent of transcriptional activity or transactivational capacity. By bioinformatics analysis, using a publicly available dataset of patients with AML, we could also confirm the altered translational control in those patients carrying the t(6;9) translocation. By sequence analysis of DEK-NUP214, a consensus-binding motif for the eukaryotic initiation factor 4E (eIF?E) was revealed. The eIF4E protein is considered the most important factor during translational initiation as well as being crucial for nucleocytoplasmic export of specific transcript important for cell proliferation, differentiation and apoptosis. We have identified a direct interaction between DEK-NUP214 and eIF4E, indicating a link between the functions of eIF4E and the dysregulated mRNA translation caused by DEK-NUP214. Furthermore, we suggest that the increased protein synthesis caused by DEK-NUP214 is the result of dysregulated nucleocytoplasmic functions of eIF4E based on interaction studies, overexpression of the negative regulator of eIF4E, the proline-rich homeodomain protein (PRH), and treatment with leptomycin B. Moreover, we have also discovered a myeloid specificity of the effect on protein synthesis caused by DEK-NUP214, concordant with the tissue-specific expression pattern of PRH, suggesting a cell context specific regulation of the functions of eIF4E. In conclusion, we have revealed the first dysregulated cellular mechanism caused by the leukemia-associated fusion protein DEK-NUP214 in myeloid cells. Altered mRNA translation is strongly implicated in tumorigenesis and is likely to be involved in the malignant transformation of DEK-NUP214 expressing cells. The increasing availability of substances interfering with translational regulation could lead to altered and improved therapy of AML patient with the t(6;9) translocation.