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Crosstalk between 14-3-3θ and AF4 enhances MLL-AF4 activity and promotes leukemia cell proliferation

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Abstract

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.

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Acknowledgements

We are grateful to Jean Ann Gilder (Scientific Communication srl, Naples, Italy) for revising and editing the text and Vittorio Lucignano, CEINGE-Biotecnologie Avanzate, for technical assistance. This work was supported by Italian Ministry of Health [RF-2011-02349269 to GE]. We are also grateful to AIL Onlus for supporting research in the field of leukemias. Tiziana Fioretti and Armando Cevenini performed and supervised the experimental analyses, evaluated the overall data and drafted the manuscript. Mariateresa Zanobio, Maddalena Raia and Daniela Sarnataro contributed to experimental and data analyses. Francesco Salvatore supervised the entire study and performed a critical review of the manuscript. Gabriella Esposito designed, coordinated and supervised the entire study, and contributed to draft and revise the manuscript.

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Authors and Affiliations

  1. IRCCS SDN, 80143, Naples, Italy

    Tiziana Fioretti, Francesco Salvatore & Gabriella Esposito

  2. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via S. Pansini 5, 80131, Naples, Italy

    Armando Cevenini, Mariateresa Zanobio, Daniela Sarnataro & Gabriella Esposito

  3. CEINGE Biotecnologie Avanzate s.c.a r.l., 80143, Naples, Italy

    Armando Cevenini, Maddalena Raia, Daniela Sarnataro & Francesco Salvatore

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  1. Tiziana Fioretti
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Fioretti, T., Cevenini, A., Zanobio, M. et al. Crosstalk between 14-3-3θ and AF4 enhances MLL-AF4 activity and promotes leukemia cell proliferation. Cell Oncol. 42, 829–845 (2019). https://doi.org/10.1007/s13402-019-00468-6

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