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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References
Akerblad P, Rosberg M, Leanderson T and Sigvardsson M . (1999). Mol. Cell. Biol., 19, 392–401.
Bieche I, Parfait B, Laurendeau I, Girault I, Vidaud M and Lidereau R . (2001). Oncogene, 20, 8109–8115.
Bond HM, Mesuraca M, Carbone E, Bonelli P, Agosti V, Amodio N, De Rosa G, Di Nicola M, Gianni A, Moore MS, Hata A, Grieco M, Morrone G and Venuta S . (2004). Blood, 103, 2062–2070.
Campbell KS, Hager EJ, Friedrich RJ and Cambier JC . (1991). Proc. Natl. Acad. Sci. USA, 88, 3982–3986.
Donis-Hernandez FR, Parkhouse ME and Santos-Argumedo L . (2001). Eur. J. Immunol., 31, 1261–1267.
Engel P, Zhou L, Ord D, Sato S, Koller B and Tedder T . (1995). Immunity, 3, 39–50.
Gilbert D, Neumann P, Taylor B, Jenkins N and Copeland N . (1993). J. Virol., 67, 2083–2090.
Gisler R, Akerblad P and Sigvardsson M . (1999). Mol. Immunol., 36, 1067–1077.
Gisler R, Jacobsen SE and Sigvardsson M . (2000). Blood, 96, 1457–1464.
Greenbaum S and Zhuang Y . (2002). Semin. Immunol., 14, 405–414.
Hagman J, Belanger C, Travis A, Turck CW and Grosschedl R . (1993). Genes Dev., 7, 760–773.
Hansen GM, Skapura D and Justice MJ . (2000). Genome Res., 10, 237–243.
Hase H, Kanno Y, Kojima M, Hasegawa K, Sakurai D, Kojima H, Tsuchiya N, Tokunaga K, Masawa N, Azuma M, Okumura K and Kobata T . (2004). Blood, 103, 2257–2265.
Hasegawa M, Fujimoto M, Poe JC, Steeber DA and Tedder TF . (2001). J. Immunol., 167, 3190–3200.
Hata A, Seoane J, Lagna G, Montalvo E, Hemmati-Brivanlou A and Massague J . (2000). Cell, 100, 229–240.
Kronenberg M, Goverman J, Haars R, Malissen M, Kraig E, Phillips L, Delovitch T, Suciu-Foca N and Hood L . (1985). Nature, 313, 647–653.
Justice MJ, Morse HR, Jenkins N and Copeland N . (1994). J. Virol., 68, 1293–1300.
Lund FE, Muller-Steffner HM, Yu N, Stout CD, Schuber F and Howard MC . (1999). J. Immunol., 162, 2693–2702.
Lund FE, Yu N, Kim K-M, Reth M and Howard MC . (1996). J. Immunol., 157, 1455–1467.
Maier H and Hagman J . (2002). Semin. Immunol., 14, 4154–4422.
Mucenski M, Bedigian H, Shull M, Copeland N and Jenkins N . (1988). J. Virol., 62, 839–846.
Mucenski M, Gilbert D, Taylor B, Jenkins N and Copeland N . (1987). Oncogene Res., 2, 33–48.
Mucenski M, Taylor B, Jenkins N and Copeland N . (1986). Mol. Cell. Biol., 6, 4236–4243.
Nutt SL, Morrison AM, Dörfler P, Rolink A and Busslinger M . (1998). EMBO J., 17, 2319–2333.
Nutt SL, Urbanek P, Rolink A and Busslinger M . (1997). Genes Dev., 11, 476–491.
O'Riordan M and Grosschedl R . (1999). Immunity, 11, 21–31.
Schebesta M, Heavey B and Busslinger M . (2002). Curr. Opin. Immunol., 14, 216–223.
Schountz T, Kasselman J, Martinson F, Brown L and Murray J . (1996). J. Immunol., 157, 3893–3901.
Shim S, Bae N and Han JK . (2002). Nucleic Acids Res., 30, 3107–3117.
Sigvardsson M, Clark DR, Fitzsimmons D, Doyle M, Akerblad P, Breslin T, Bilke S, Li R, Yeamans C, Zhang G and Hagman J . (2002). Mol. Cell. Biol., 22, 8539–8551.
Sigvardsson M, O'Riordan M and Grosschedl R . (1997). Immunity, 7, 25–36.
Smith EMK, Gisler R and Sigvardsson M . (2002). J. Immunol., 169, 261–270.
Suzuki T, Shen H, Akagi K, Morse HC, Malley JD, Naiman DQ, Jenkins NA and Copeland NG . (2002). Nat. Genet., 32, 166–174.
Tsai RY and Reed RR . (1997). J. Neurosci., 17, 4159–4169.
Tsai RY and Reed RR . (1998). Mol. Cell. Biol., 18, 6447–6456.
Wang SS, Tsai RY and Reed RR . (1997). J. Neurosci., 17, 4149–4158.
Warming S, Liu P, Suzuki T, Akagi K, Lindtner S, Pavlakis GN, Jenkins NA and Copeland NG . (2003). Blood, 101, 1934–1940.
Xu Y, Beavvitt S-JE, Harder KW, Hibbs ML and Tarlington DM . (2002). J. Immunol., 169, 6910–6918.
Zhou L, Ord D, Hughes A and Tedder T . (1991). J. Immunol., 147, 1424–1432.
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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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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DOI: https://doi.org/10.1038/sj.onc.1208243
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