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  • Original Paper
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Evi3, a zinc-finger protein related to EBFAZ, regulates EBF activity in B-cell leukemia

Abstract

Retroviral insertions that activate proto-oncogenes are a primary cause of tumors in certain strains of mice. The AKXD recombinant inbred mice are predisposed to a variety of leukemias and lymphomas as a result of viral integration. One common insertion site, the ecotropic viral insertion site 3 (Evi3), has been implicated in most B-cell tumors in the AKXD-27 strain. The Evi3 gene encodes a zinc-finger protein with sequence similarity to the Early B-cell Factor-Associated Zinc-finger gene (EBFAZ). We show that the Evi3 gene is overexpressed in several tumors with viral insertions at Evi3, which results in the upregulation of Early B-cell Factor (EBF)-target gene expression, suggesting that Evi3 modulates EBF activity. Reconstitution of primary leukemia cells showed that these tumors express high densities of the B-cell surface proteins CD19 and CD38, which are EBF targets. Using a transactivation assay, we show that the terminal six zinc-fingers of Evi3 are required for modification of EBF activity. This is the first evidence that Evi3 expression in tumors alters the level of EBF target genes, and the first characterization of the Evi3 protein domains required for modulation of EBF activity. Further, these data imply that Evi3 misexpression initiates tumorigenesis by perturbing B-cell development via an interaction with EBF.

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Acknowledgements

We thank Dr Mikael Sigvardsson for the myc-EBF, myc vector, and B29-luciferase constructs. We thank Toni L Jago, Shamsha Damani, Antoine Perchellet, and Mary E Stech for superb technical assistance. We thank D Popp for technical assistance with FACS analysis and G Hansen for assistance in tumor processing. We thank Dr Yuan Zhuang for critical reading of the manuscript. Tumor insertion site sequences and chromosomal location can be viewed at: http://www.mouse-genome.bcm.tmc.edu/vstdata/. This work was supported by PHS grants R01 CA63229 to MJJ and F32 HD42436 to KEH.

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Correspondence to Monica J Justice.

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Hentges, K., Weiser, K., Schountz, T. et al. Evi3, a zinc-finger protein related to EBFAZ, regulates EBF activity in B-cell leukemia. Oncogene 24, 1220–1230 (2005). https://doi.org/10.1038/sj.onc.1208243

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