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  • Original Paper
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An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia

Oncogene volume 21, pages 5981–5989 (2002)Cite this article

Abstract

To date, constitutively activating point mutations reported in hematopoietic growth factor receptors in patients with acute myeloid leukemia (AML) have been restricted to receptors with intrinsic tyrosine kinase activity such as c-kit and FLT3. We describe here a Thr617Asn mutation in the transmembrane domain of the non-tyrosine kinase receptor for granulocyte colony-stimulating factor (G-CSF) in the blast cells of two out of 555 AML patients examined. The mutant receptor conferred growth factor independence on factor-dependent Ba/F3 cells. In the absence of ligand, immunoblotting showed weak phosphorylation of JAK2, STAT3, ERKs 1 and 2 and the receptor itself, and there was approximately 70% of maximal growth in a proliferation assay. All signals were significantly enhanced in the presence of G-CSF. Retroviral transduction of mutant receptor into primary hematopoietic CD34+ cells induced G-CSF independent myeloid differentiation as assessed by the development of neutrophils and surface expression of CD11b and CD14. These results confirm the importance of the transmembrane domain for receptor function and suggest that introduction of an asparagine residue can cause sufficient stabilization of helix–helix interactions in the absence of ligand to activate downstream signaling pathways involved in directing proliferation and differentiation.

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References

  • Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT . 2001 Br. J. Haematol. 113: 983–988

  • Alexander WS, Metcalf D, Dunn AR . 1995 EMBO J. 14: 5569–5578

  • Alexander WS, Nicola NA . 1998 Leuk. Res. 22: 1097–1111

  • Bargmann CI, Hung MC, Weinberg RA . 1986 Cell 45: 649–657

  • Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Morra E, Mecucci C . 2000 Blood 95: 726–727

  • Bernard T, Gale RE, Linch DC . 1996 Br. J. Haematol. 93: 527–533

  • Bernstein ID, Andrews RG, Zsebo KM . 1991 Blood 77: 2316–2321

  • Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell Jr JE . 1999 Cell 98: 295–303

  • Byrne JL, Marshall CJ . 1998 Br. J Haematol. 100: 256–264

  • Choma C, Gratkowski H, Lear JD, DeGrado WF . 2000 Nat. Struct. Biol. 7: 161–166

  • Dong F, Liu X, de Koning JP, Touw IP, Henninghausen L, Larner A, Grimley PM . 1998 J. Immunol. 161: 6503–6509

  • Farr CJ, Saiki RK, Erlich HA, McCormick F, Marshall CJ . 1988 Proc. Natl. Acad. Sci. USA 85: 1629–1633

  • Gonda TJ, D'Andrea RJ . 1997 Blood 89: 355–369

  • Heldin CH . 1995 Cell 80: 213–223

  • Ihle JN . 1996 Adv. Cancer Res. 68: 23–65

  • Ilaria RL, Hawley RG, Van Etten RA . 1999 Blood 93: 4154–4166

  • Jenkins BJ, Blake TJ, Gonda TJ . 1998 Blood 92: 1989–2002

  • Jenkins BJ, D'Andrea R, Gonda TJ . 1995 EMBO J. 14: 4276–4287

  • Kelly PF, Vandergriff J, Nathwani A, Nienhuis AW, Vanin EF . 2000 Blood 96: 1206–1214

  • Kitamura T, Onishi M, Yahata T, Kanakura Y, Asano S . 1998 Blood 92: 2596–2597

  • Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R, Ueda R . 1999 Blood 93: 3074–3080

  • Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, Wheatley K, Bowen DT, Burnett AK, Goldstone AH, Linch DC . 2001 Blood 98: 1752–1759

  • Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC . 2002 Blood (in press)

  • Livnah O, Stura EA, Middleton SA, Johnson DL, Jolliffe LK, Wilson IA . 1999 Science 283: 987–990

  • McKinstry WJ, Li CL, Rasko JE, Nicola NA, Johnson GR, Metcalf D . 1997 Blood 89: 65–71

  • McLemore ML, Grewal S, Liu F, Archambault A, Poursine-Laurent J, Haug J, Link DC . 2001 Immunity 14: 193–204

  • Molineux G, Migdalska A, Szmitkowski M, Zsebo K, Dexter TM . 1991 Blood 78: 961–966

  • Nakano Y, Kiyoi H, Miyawaki S, Asou N, Ohno R, Saito H, Naoe T . 1999 Br. J. Haematol. 104: 659–664

  • Onishi M, Mui AL, Morikawa Y, Cho L, Kinoshita S, Nolan GP, Gorman DM, Miyajima A, Kitamura T . 1996 Blood 88: 1399–1406

  • Persons DA, Allay JA, Allay ER, Ashmun RA, Orlic D, Jane SM, Cunningham JM, Nienhuis AW . 1999 Blood 93: 488–499

  • Persons DA, Mehaffey MG, Kaleko M, Nienhuis AW, Vanin EF . 1998 Blood Cells Mol. Dis. 24: 167–182

  • Remy I, Wilson IA, Michnick SW . 1999 Science 283: 990–993

  • Robertson SC, Tynan JA, Donoghue DJ . 2000 Trends Genet. 16: 265–271

  • Shimozaki K, Nakajima K, Hirano T, Nagata S . 1997 J. Biol. Chem. 272: 25184–25199

  • Shinjo K, Takeshita A, Ohnishi K, Ohno R . 1995 Br. J. Haematol. 91: 783–794

  • Ward AC, Smith L, de Koning JP, van Aesch Y, Touw IP . 1999 J. Biol. Chem. 274: 14956–14962

  • Watowich SS, Hilton DJ, Lodish HF . 1994 Mol. Cell. Biol. 14: 3535–3549

  • Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T . 2001 Blood 97: 2434–2439

  • Yoshimura A, Longmore G, Lodish HF . 1990 Nature 348: 647–649

  • Zaliauskiene L, Kang S, Brouillette CG, Lebowitz J, Arani RB, Collawn JF . 2000 Mol. Biol. Cell. 11: 2643–2655

  • Zhou FX, Cocco MJ, Russ WP, Brunger AT, Engelman DM . 2000 Nat. Struct. Biol. 7: 154–160

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Author notes

  1. Louisa V Forbes and Rosemary E Gale: The first two authors contributed equally to this work

Authors and Affiliations

  1. Department of Haematology, University College London, London, WC1E 6HX, UK

    Louisa V Forbes, Rosemary E Gale, Arnold Pizzey, Karin Pouwels, Amit Nathwani & David C Linch

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  1. Louisa V Forbes
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  2. Rosemary E Gale
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  3. Arnold Pizzey
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  5. Amit Nathwani
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  6. David C Linch
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Correspondence to Rosemary E Gale.

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Forbes, L., Gale, R., Pizzey, A. et al. An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia. Oncogene 21, 5981–5989 (2002). https://doi.org/10.1038/sj.onc.1205767

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  • DOI: https://doi.org/10.1038/sj.onc.1205767

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