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  • Original Paper
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Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

Oncogene volume 19, pages 624–631 (2000)Cite this article

Abstract

We have recently identified an internal tandem duplication of the human Flt3 gene in approximately 20% of acute myeloid leukemia (AML) cases. In the present study, the wild-type and the mutant Flt3 genes were transfected into two IL-3-dependent cell lines, 32D and BA/F3 cells. Mutant Flt3-transfected cells exhibited autonomous growth while wild-type Flt3-transfected cells with the continuous stimulation of Flt3 ligand exhibited a minimal proliferation. Cells expressing mutant Flt3 showed constitutive activation of STAT5 and MAP kinase. In contrast, Flt3 ligand stimulation caused rapid activation of MAP kinase but not STAT5 in cells expressing wild-type Flt3. Finally, we found constitutive activation of MAP kinase and STAT5 in all clinical samples of AML patients with mutant Flt3. Our study shows the significance of internal tandem duplication of Flt3 receptors for leukemia cell expansion.

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References

  • Adachi T, Pazdrak K, Stanfford S and Alam R. . 1999 J. Immunol. 162: 1496–1501.

  • Brodsky AR, Mukhina LG, Nelson LK, Lawrence ST, Jones JR and Buckley TJ. . 1999 Blood 93: 1749–1756.

  • Cadena DL and Gill GN. . 1992 FASEB J. 6: 2332–2337.

  • Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N and Miura O. . 1998 Blood 91: 3734–3745.

  • Drexler HG. . 1996 Leukemia 10: 588–599.

  • Dumon S, Santos SC, Debierre-Grockiego F, Gouilleux-Gruart V, Cocault L, Boucheron C, Mollat P, Gisselbrecht S and Gouilleux F. . 1999 Oncogene 18: 4191–4199.

  • Hayakawa F, Towatari M, Iida H, Wakao H, Kiyoi H, Naoe T and Saito H. . 1998 Br. J. Haematol. 101: 521–528.

  • Horiike S, Yokota S, Nakao M, Iwai T, Sasai Y, Kaneko H, Taniwaki M, Kashima K, Fujii H, Abe T and Misawa S. . 1997 Leukemia 11: 1442–1446.

  • Kiyoi H, Towatari M, Yokota S, Ohno R, Saito H and Naoe T. . 1998 Leukemia 12: 1333–1337.

  • Lavagna-Sèvenier C, Marchetto S, Birnbaum D and Rosnet O. . 1998a Leukemia 12: 301–310.

  • Lavagna-Sèvenier C, Marchetto S, Birnbaum D and Rosnet O. . 1998b J. Biol. Chem. 273: 14962–14967.

  • Lisovsky M, Estrov Z, Zhang X, Consoli U, Sanchez-Williams G, Snell V, Munker R, Goodacre A, Savchenko V and Andreeff M. . 1996 Blood 88: 3987–3997.

  • Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP and Lemischka IR. . 1995 Immunity 3: 147–161.

  • Matsumura I, Kitamura T, Wakao H, Tanaka H, Hashimoto K, Albanese C, Downward J, Pestell GR and Kanakura Y. . 1999 EMBO J. 18: 1367–1377.

  • Matthews W, Jordan C, Wiegand G, Pardoll D and Lemischla I. . 1991 Cell 65: 1143–1152.

  • Mercedes D, Shulin W and Ihor RL. . 1993 Mol. Cell. Biol. 13: 6572–6585.

  • McKenna HJ, Smith FO, Brasel K, Hirschstein D, Bernstein ID, Williams DE and Lyman SD. . 1996 Exp. Hematol. 24: 378–385.

  • Mui AL, Wakao H, Kinoshita T, Kitamura T and Miyajima A. . 1996 EMBO J. 15: 2425–2433.

  • Pang L, Sawada T, Decker SJ and Saltiel AR. . 1995 J. Biol. Chem. 270: 13585–13588.

  • Perkins GR, Marshall CJ and Collins MKL. . 1996 Blood 87: 3669–3675.

  • Piacibello W, Fubine L, Sanavio F, Brizzi MF, Severino S, Garetto L, Stacchini A, Pegoraro L and Aglietta M. . 1995 Blood 86: 4105–4114.

  • Rosnet O, Marchetto S, de Lapeyriere O and Birnbaum D. . 1991a Oncogene 6: 1641–1650.

  • Rosnet O, Mattei MG, Marchetto S and Birnbaum D. . 1991b Genomic 9: 380–385.

  • Rosnet O, Schiff C, Pébusque MJ, Marchetto S, Tonnelle C, Toiron Y, Birg F and Birnbaum D. . 1993 Blood 82: 1110–1119.

  • Socolovsky M, Fallon JEA, Wang S, Brugnara C and Lodish FH. . 1999 Cell 98: 181–191.

  • Torigoe T, O'Connor R, Santoli D and Reed JC. . 1992 Blood 80: 617–624.

  • Towatari M, Iida H, Tanimoto M, Iwata H, Hamaguchi M and Saito H. . 1997 Leukemia 11: 479–484.

  • Valgeirsdóttir S, Paukku K, Silvennoinen O, Heldin C-H and Claesson-Welsh L. . 1998 Oncogene 16: 505–515.

  • Vignais M-L, Sadowski HB, Watling D and Rogers NC. . 1996 Mol. Cell. Biol. 16: 1759–1769.

  • Wakao H, Gouilleux F and Groner B. . 1994 EMBO J. 13: 2182–2191.

  • Wen Z, Zhong Z and Darnell Jr EJ. . 1995 Cell 82: 241–250.

  • Yarden Y and Ullrich A. . 1988 Annu. Rev. Biochem. 57: 443–478.

  • Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T, Sonoda Y, Abe T, Kashima K, Matuo Y and Naoe T. . 1997 Leukemia 11: 1605–1609.

  • Zhang S, Mantel C and Broxmeyer HE. . 1999 J. Leukoc. Biol. 65: 372–380.

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Acknowledgements

The authors thank Dr O Rosnet for providing the Flt3 cDNA clone, and S Suzuki and C Wakamatsu for their technical assistance. Murine IL-3 was provided by Kirin Brewery Co. This work was supported by grants-in-aid from the Public Trust Haraguchi Memorial Cancer Research Fund, Kanae Foundation for Life and Socio-Medical Science, Uehara Memorial Foundation and Osaka Cancer Research Foundation.

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Authors and Affiliations

  1. First Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, 466-8550, Nagoya, Japan

    Fumihiko Hayakawa, Masayuki Towatari, Mitsune Tanimoto & Hidehiko Saito

  2. Department of Infectious Diseases, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, 466-8550, Nagoya, Japan

    Hitoshi Kiyoi & Tomoki Naoe

  3. Department of Hemopoietic Factors, The Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108, Japan

    Toshio Kitamura

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  1. Fumihiko Hayakawa
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Hayakawa, F., Towatari, M., Kiyoi, H. et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 19, 624–631 (2000). https://doi.org/10.1038/sj.onc.1203354

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