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Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain

Oncogene volume 21, pages 2555–2563 (2002)Cite this article

Abstract

Internal tandem duplication (ITD) of the juxtamembrane (JM) domain of FLT3 is the most frequent mutation in human acute myeloid leukemia, and is significantly associated with leukocytosis and a poor prognosis. Previously we reported that FLT3 with ITD (FLT3/ITD) formed a homodimer and was autophosphorylated on tyrosine residues, while the mechanism remains unclear. In this study, we elucidated the role of the JM domain in FLT3 activation. Mutant FLT3 with not only ITD but also an elongating or shortening JM domain transformed murine IL3-dependent myeloid progenitor cell line 32D regardless of the tyrosine residues in the JM domain. These mutant FLT3s were constitutively tyrosine phosphorylated and activated signal-transduction molecules such as SHC, MAP kinase and STAT5a. Notably, co-transfection of the truncated FLT3/ITD lacking kinase and C-terminal domains with the wild type (Wt)-FLT3 into 32D cells resulted in the autonomous proliferation. In these cells, truncated FLT3/ITD generated a hetero-complex with Wt-FLT3 and Wt-FLT3 was constitutively tyrosine phosphorylated. These findings indicate that the FLT3 JM domain plays an important role in receptor activation, and that the length-mutated JM domain induces ligand-independent receptor activation but also activates Wt-FLT3 in a trans-manner.

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Acknowledgements

This work was supported by Grants-in-Aid from the Japanese Ministry of Health, Labour and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, Novartis Foundation for the Promotion of Science and Uehara Memorial Foundation. We thank Dr Oliver Rosnet, Dr Toshio Kitamura and Kirin Brewery Co. Ltd. for providing us with materials, and Dr Manabu Ninomiya, Ms Yoko Kudo and Ms Yoko Tagawa for technical and secretarial assistance.

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Authors and Affiliations

  1. Department of Infectious Diseases, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan

    Hitoshi Kiyoi & Tomoki Naoe

  2. Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan

    Ryuzo Ohno

  3. Second Department of Medicine, Nagoya City University, Nagoya, 467-8601, Japan

    Ryuzo Ueda

  4. Department of Medicine, Nagoya National Hospital, Nagoya, 460-0001, Japan

    Hidehiko Saito

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  1. Hitoshi Kiyoi
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  2. Ryuzo Ohno
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  3. Ryuzo Ueda
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  4. Hidehiko Saito
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  5. Tomoki Naoe
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Correspondence to Hitoshi Kiyoi.

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Kiyoi, H., Ohno, R., Ueda, R. et al. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene 21, 2555–2563 (2002). https://doi.org/10.1038/sj.onc.1205332

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