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Crosstalk between 14-3-3θ and AF4 enhances MLL-AF4 activity and promotes leukemia cell proliferation.
Cellular Oncology ( IF 6.6 ) Pub Date : 2019-09-06 , DOI: 10.1007/s13402-019-00468-6 Tiziana Fioretti 1 , Armando Cevenini 2, 3 , Mariateresa Zanobio 2 , Maddalena Raia 3 , Daniela Sarnataro 2, 3 , Francesco Salvatore 1, 3 , Gabriella Esposito 1, 2
中文翻译:
14-3-3θ 和 AF4 之间的串扰增强 MLL-AF4 活性并促进白血病细胞增殖。
更新日期:2019-09-06
Cellular Oncology ( IF 6.6 ) Pub Date : 2019-09-06 , DOI: 10.1007/s13402-019-00468-6 Tiziana Fioretti 1 , Armando Cevenini 2, 3 , Mariateresa Zanobio 2 , Maddalena Raia 3 , Daniela Sarnataro 2, 3 , Francesco Salvatore 1, 3 , Gabriella Esposito 1, 2
Affiliation
Purpose
The t(4;11)(q21;q23) translocation characterizes a form of acute lymphoblastic leukemia with a poor prognosis. It results in a fusion gene encoding a chimeric transcription factor, MLL-AF4, that deregulates gene expression through a variety of still controversial mechanisms. To provide new insights into these mechanisms, we examined the interaction between AF4, the most common MLL fusion partner, and the scaffold protein 14-3-3θ, in the context of t(4;11)-positive leukemia.Methods
Protein-protein interactions were analyzed using immunoprecipitation and in vitro binding assays, and by fluorescence microscopy in t(4;11)-positive RS4;11 and MV4–11 leukemia cells and in HEK293 cells. Protein and mRNA expression levels were determined by Western blotting and RT-qPCR, respectively. A 5-bromo-2′-deoxyuridine assay and an annexin V/propidium iodide assay were used to assess proliferation and apoptosis rates, respectively, in t(4;11)-positive and control cells. Chromatin immunoprecipitation was performed to assess binding of 14-3-3θ and AF4 to a specific promoter element.Results
We found that AF4 and 14-3-3θ are nuclear interactors, that 14-3-3θ binds Ser588 of AF4 and that 14-3-3θ forms a complex with MLL-AF4. In addition, we found that in t(4;11)-positive cells, 14-3-3θ knockdown decreased the expression of MLL-AF4 target genes, induced apoptosis and hampered cell proliferation. Moreover, we found that 14-3-3θ knockdown impaired the recruitment of AF4, but not of MLL-AF4, to target chromatin. Overall, our data indicate that the activity of the chimeric transcription factor MLL-AF4 depends on the cellular availability of 14-3-3θ, which triggers the transactivating function and subsequent degradation of AF4.Conclusions
From our data we conclude that the scaffold protein 14-3-3θ enhances the aberrant activity of the chimeric transcription factor MLL-AF4 and, therefore, represents a new player in the molecular pathogenesis of t(4;11)-positive leukemia and a new promising therapeutic target.中文翻译:
14-3-3θ 和 AF4 之间的串扰增强 MLL-AF4 活性并促进白血病细胞增殖。