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Functional contribution of EEN to leukemogenic transformation by MLL-EEN fusion protein

Oncogene volume 23, pages 3385–3394 (2004)Cite this article

Abstract

The EEN (extra eleven nineteen) gene was originally cloned from a case of acute myeloid leukemia M5 subtype with translocation t (11; 19)(q23; p13), in which EEN was fused with MLL. To explore the involvement of EEN in leukemogenesis caused by MLL-EEN, we studied the transformation potential of the MLL-EEN fusion protein. MLL-EEN had oncogenic features, while, as a control, MLLΔ, the truncated form of MLL lacking the EEN moiety, did not show any oncogenic potential. MLL-EEN exerted a dominant-negative effect over wild-type EEN in terms of subcellular localization. Normally, EEN was found in the cytoplasm, but the MLL-EEN fusion protein was located in the nucleus, and EEN could be delocalized by MLL-EEN. This interaction is via a coiled-coil dimerization domain of EEN, which is reserved in the fusion protein. In addition, MLL-EEN might act as a potential transcriptional factor with the MLL part providing the DNA-binding domain and the EEN part providing the transcription activation domain, though EEN seems to have no direct role in transcriptional regulation. As an aberrant transcriptional factor, MLL-EEN could transactivate the promoter of HoxA7, a potential target gene of MLL.

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References

  • Akao Y, Mizoguchi H, Misiura K, Stec WJ, Seto M, Ohishi N and Yagi K . (1998). Cancer Res., 58, 3773–3776.

  • Ayton PM and Cleary ML . (2001). Oncogene, 20, 5695–5707.

  • Ayton PM and Cleary ML . (2003). Genes Dev., 17, 2298–2307.

  • Birke M, Schreiner S, Garcia-Cuellar MP, Mahr K, Titgemeyer F and Slany RK . (2002). Nucleic Acids Res., 30, 958–965.

  • Butler LH, Slany R, Cui X, Cleary ML and Mason DY . (1997). Blood, 89, 3361–3370.

  • Chan LC and Yam JW . (2002). Blood, 100 (Suppl), 199b.

  • Chen Y, Deng L, Maeno-Hikichi Y, Lai M, Chang S, Chen G and Zhang JF . (2003). Cell, 115, 37–48.

  • Collins EC and Rabbitts TH . (2002). Trends Mol. Med., 8, 436–442.

  • Collins SJ . (1987). Blood, 70, 1233–1244.

  • Corral J, Lavenir I, Impey H, Warren AJ, Forster A, Larson TA, Bell S, McKenzie AN, King G and Rabbitts TH . (1996). Cell, 85, 853–861.

  • Dimartino JF, Ayton PM, Chen EH, Naftzger CC, Young BD and Cleary ML . (2002). Blood, 99, 3780–3785.

  • Dimartino JF, Miller T, Ayton PM, Landewe T, Hess JL, Cleary ML and Shilatifard A . (2000). Blood, 96, 3887–3893.

  • Dobson CL, Warren AJ, Pannell R, Forster A and Rabbitts TH . (2000). EMBO J., 19, 843–851.

  • Dorrie J, Schuh W, Keil A, Bongards E, Greil J, Fey GH and Zunino SJ . (1999). Leukemia, 13, 1539–1547.

  • Ernst P, Wang J and Korsmeyer SJ . (2002). Curr. Opin. Hematol., 9, 282–287.

  • Floyd S and De Camilli P . (1998). Trends Cell Biol., 8, 299–301.

  • Frank RC, Sun X, Berguido FJ, Jakubowiak A and Nimer SD . (1999). Oncogene, 18, 1701–1710.

  • Giachino C, Lantelme E, Lanzetti L, Saccone S, Bella VG and Migone N . (1997). Genomics, 41, 427–434.

  • Hajra A, Liu PP, Wang Q, Kelley CA, Stacy T, Adelstein RS, Speck NA and Collins FS . (1995). Proc. Natl. Acad. Sci. USA, 92, 1926–1930.

  • Hayashi Y, Honma Y, Niitsu N, Taki T, Bessho F, Sako M, Mori T, Yanagisawa M, Tsuji K and Nakahata T . (2000). Cancer Res., 60, 1139–1145.

  • Hsu K and Look AT . (2003). Cancer Cell, 4, 81–83.

  • Huret JL, Dessen P and Bernheim A . (2001). Leukemia, 15, 987–989.

  • Joh T, Kagami Y, Yamamoto K, Segawa T, Takizawa J, Takahashi T, Ueda R and Seto M . (1996). Oncogene, 13, 1945–1953.

  • Kamps MP, Look AT and Baltimore D . (1991). Genes Dev., 5, 358–368.

  • Kawagoe H, Kawagoe R and Sano K . (2001). Leukemia, 15, 1743–1749.

  • Kersey JH, Wang D and Oberto M . (1998). Leukemia, 12, 1561–1564.

  • Kitada S, Pedersen IM, Schimmer AD and Reed JC . (2002). Oncogene, 21, 3459–3474.

  • Kwon KB, Park EK, Ryu DG and Park BH . (2002). Exp. Mol. Med., 34, 32–37.

  • Lanza C, Gaidano G, Cimino G, Pastore C, Nomdedeu J, Volpe G, Vivenza C, Parvis G, Mazza U, Basso G, Madon E, Lo CF and Saglio G . (1996). Genes Chromosomes Cancer, 15, 48–53.

  • Lavau C, Du C, Thirman M and Zeleznik-Le N . (2000). EMBO J., 19, 4655–4664.

  • Lavau C, Szilvassy SJ, Slany R and Cleary ML . (1997). EMBO J., 16, 4226–4237.

  • Mahgoub N, Parker RI, Hosler MR, Close P, Winick NJ, Masterson M, Shannon KM and Felix CA . (1998). Genes Chromosomes Cancer, 21, 270–275.

  • Martin ME, Milne TA, Bloyer S, Galoian K, Shen W, Gibbs D, Brock HW, Slany R and Hess JL . (2003). Cancer Cell, 4, 197–207.

  • Mayer BJ . (2001). J. Cell Sci., 114, 1253–1263.

  • McPherson PS . (1999). Cell Signal., 11, 229–238.

  • Mollinedo F, Santos-Beneit AM and Gajate C . (1998). Animal Cell Culture Techniques. Clynes M (ed). Springer-Verlag: New York, pp. 264–297.

  • Nakamura T, Largaespada DA, Shaughnessy Jr JD, Jenkins NA and Copeland NG . (1996). Nat. Genet., 12, 149–153.

  • Naoe T, Kubo K, Kiyoi H, Ohno R, Akao Y, Yoshida J, Kato K, Kojima S and Matsuyama T . (1993). Blood, 82, 2260–2261.

  • Niitsu N, Hayashi Y and Honma Y . (2001). Oncogene, 20, 375–384.

  • Ormerod MG . (1998). Leukemia, 12, 1013–1025.

  • Petrelli A, Gilestro GF, Lanzardo S, Comoglio PM, Migone N and Giordano S . (2002). Nature, 416, 187–190.

  • Pocock CF, Malone M, Booth M, Evans M, Morgan G, Greil J and Cotter FE . (1995). Br. J. Haematol., 90, 855–867.

  • Polak PE, Simone F, Kaberlein JJ, Luo RT and Thirman MJ . (2003). Mol. Biol. Cell, 14, 1517–1528.

  • Reutens AT and Begley CG . (2002). Int. J. Biochem. Cell Biol., 34, 1173–1177.

  • Ringstad N, Nemoto Y and De Camilli P . (1997). Proc. Natl. Acad. Sci. USA, 94, 8569–8574.

  • Ringstad N, Nemoto Y and De Camilli P . (2001). J. Biol. Chem., 276, 40424–40430.

  • Rogaia D, Grignani F, Carbone R, Riganelli D, LoCoco F, Nakamura T, Croce CM, Di Fiore PP and Pelicci PG . (1997). Cancer Res., 57, 799–802.

  • Rowley JD . (1998). Annu. Rev. Genet., 32, 495–519.

  • Rubnitz JE, Behm FG and Downing JR . (1996). Leukemia, 10, 74–82.

  • Schichman SA, Caligiuri MA, Gu Y, Strout MP, Canaani E, Bloomfield CD and Croce CM . (1994). Proc. Natl. Acad. Sci. USA, 91, 6236–6239.

  • Schreiner SA, Garcia-Cuellar MP, Fey GH and Slany RK . (1999). Leukemia, 13, 1525–1533.

  • Simone F, Polak PE, Kaberlein JJ, Luo RT, Levitan DA and Thirman MJ . (2001). Blood, 98, 201–209.

  • Slany RK, Lavau C and Cleary ML . (1998). Mol. Cell Biol., 18, 122–129.

  • So CW, Caldas C, Liu MM, Chen SJ, Huang QH, Gu LJ, Sham MH, Wiedemann LM and Chan LC . (1997). Proc. Natl. Acad. Sci. USA, 94, 2563–2568.

  • So CW and Cleary ML . (2002). Mol. Cell Biol., 22, 6542–6552.

  • So CW and Cleary ML . (2003). Blood, 101, 633–639.

  • So CW, Lin M, Ayton PM, Chen EH and Cleary ML . (2003). Cancer Cell, 4, 99–110.

  • Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY and Dikic I . (2002). Nature, 416, 183–187.

  • Sparks AB, Hoffman NG, McConnell SJ, Fowlkes DM and Kay BK . (1996). Nat. Biotechnol., 14, 741–744.

  • Trayner ID, Bustorff T, Etches AE, Mufti GJ, Foss Y and Farzaneh F . (1998). Leuk. Res., 22, 537–547.

  • Yam JW, Jin DY, So CW and Chan LC . (2003). Blood, DOI:10.1182/blood-2003-07-2452.

  • Yano T, Nakamura T, Blechman J, Sorio C, Dang CV, Geiger B and Canaani E . (1997). Proc. Natl. Acad. Sci. USA, 94, 7286–7291.

  • Yu BD, Hess JL, Horning SE, Brown GA and Korsmeyer SJ . (1995). Nature, 378, 505–508.

  • Zeisig BB, Schreiner S, Garcia-Cuellar MP and Slany RK . (2003). Leukemia, 17, 359–365.

  • Zeleznik L, Harden AM and Rowley JD . (1994). Proc. Natl. Acad. Sci. USA, 91, 10610–10614.

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Acknowledgements

We are grateful to Robert Karl Slany for the gift of the pGL3-HoxA7 plasmid. We thank Jian-Xiang Liu for critical reading of this manuscript. We greatly appreciate the technical assistance of Ting Wang and the members in Shanghai Institute of Hematology. This work was supported in part by grants from the Chinese National Key Program for Basic Research (973), the National Natural Science Foundation of China, the Shanghai Commission for Science and Technology, the Shanghai Commission for Education and the Samuel Waxman Cancer Research Foundation.

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  1. Han Liu, Bing Chen and Hui Xiong: These authors contributed equally to this work

Authors and Affiliations

  1. State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Second Medical University, 197 Ruijin Road II, Shanghai, 200025, PR China

    Han Liu, Bing Chen, Hui Xiong, Qiu-Hua Huang, Qing-Hua Zhang, Zhu-Gang Wang, Zhu Chen & Sai-Juan Chen

  2. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai, 200031, PR China

    Han Liu & Bo-Liang Li

  3. Chinese National Human Genome Center at Shanghai, 351 Guo Shou Jing Road, Shanghai, 201203, PR China

    Zhu Chen

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Correspondence to Sai-Juan Chen.

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Liu, H., Chen, B., Xiong, H. et al. Functional contribution of EEN to leukemogenic transformation by MLL-EEN fusion protein. Oncogene 23, 3385–3394 (2004). https://doi.org/10.1038/sj.onc.1207402

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