Transcriptional regulation of the proto-oncogene Zfp521 by SPI1 (PU.1) and HOXC13

Ming Yu, Salma Al-Dallal, Latifa Al-Haj , Shiraj Panjwani, Akina S McCartney , Sarah Edwards, Pooja Manjunath, Catherine Walker, Alexander Awgulewitsch , Kathryn Hentges

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The mouse zinc-finger gene Zfp521 (also known as ecotropic viral insertion site 3; Evi3; and ZNF521 in humans) has been identified as a B-cell proto-oncogene, causing leukaemia in mice following retroviral insertions in its promoter region that drive Zfp521 over-expression. Furthermore, ZNF521 is expressed in human haematopoietic cells, and translocations between ZNF521 and PAX5 are associated with paediatric acute lymphoblastic leukaemia. However, the regulatory factors that control Zfp521 expression directly have not been characterised. Here we demonstrate that the transcription factors SPI1 (PU.1) and HOXC13 synergistically regulate Zfp521 expression, and identify the regions of the Zfp521 promoter required for this transcriptional activity. We also show that SPI1 and HOXC13 activate Zfp521 in a dose-dependent manner. Our data support a role for this regulatory mechanism in vivo, as transgenic mice over-expressing Hoxc13 in the foetal liver show a strong correlation between Hoxc13 expression levels and Zfp521 expression. Overall these experiments provide insights into the regulation of Zfp521 expression in a non-oncogenic context. The identification of transcription factors capable of activating Zfp521 provides a foundation for further investigation of the regulatory mechanisms involved in ZFP521-driven cell differentiation processes and diseases linked to Zfp521 mis-expression.
Original languageEnglish
Early online date10 Aug 2016
Publication statusPublished - 29 Aug 2016


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