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Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia

Leukemia volume 17, pages 1–8 (2003)Cite this article

Abstract

The SH2 domain-containing inositol 5′-phosphatase (SHIP) is crucial in hematopoietic development. To evaluate the possible tumor suppressor role of the SHIP gene in myeloid leukemogenesis, we examined primary leukemia cells from 30 acute myeloid leukemia (AML) patients, together with eight myeloid leukemia cell lines. A somatic mutation at codon 684, replacing Val with Glu, was detected in one patient, lying within the signature motif 2, which is the phosphatase active site. The results of an in vitro inositol 5′-phosphatase assay revealed that the mutation reduced catalytic activity of SHIP. Leukemia cells with the mutation showed enhanced Akt phosphorylation following IL-3 stimulation. K562 cells transfected with the mutated SHIP-V684E cDNA showed a growth advantage even at lower serum concentrations and resistance to apoptosis induced by serum deprivation and exposure to etoposide. These results suggest a possible role of the mutated SHIP gene in the development of acute leukemia and chemotherapy resistance through the deregulation of the phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3)/Akt signaling pathway. This is the first report of a mutation in the SHIP gene in any given human cancer, and indicates the need for more attention to be paid to this gene with respect to cancer pathogenesis.

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Acknowledgements

The human SHIP cDNA was kindly provided by Dr Hisamaru Hirai (Tokyo University). We thank Dr Haruhiko Sugimura for useful discussion and Dr Yoshinori Nozawa for critical review of the manuscript. We also thank Drs Kensuke Naito, Shinya Fujisawa, Yota Fujita, Takayuki Matui and Akihito Takeshita, for the management of patients’ samples, as well as Kumi Nishizawa and Terumi Taniguchi for technical assistance. This work was supported in part by a grant-in-aid from the Japanese Ministry of Education, Culture, Sport, and Science, and a grant from the Leukemia Study Group of the Ministry of Health, Labor, and Welfare.

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Author notes

  1. J-M Luo and H Yoshida: J-M Luo and H Yoshida contributed equally to this study

Authors and Affiliations

  1. Department of Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan

    J-M Luo, L Pan, K Shigeno & K Ohnishi

  2. Department of Genetic Diagnosis, Gifu International Institute of Biotechnology, Mitake, Japan

    H Yoshida & Y Akao

  3. Institute of Applied Biochemistry, Mitake, Japan

    S Komura & N Ohishi

  4. Second Department of Internal Medicine, Nagoya City University Medical School, Nagoya, Japan

    I Hanamura, K Miura, S Iida & R Ueda

  5. Department of Infectious Diseases, School of Medicine, Nagoya University, Nagoya, Japan

    T Naoe

  6. Aichi Cancer Center Hospital, Nagoya, Japan

    R Ohno

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Luo, JM., Yoshida, H., Komura, S. et al. Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia. Leukemia 17, 1–8 (2003). https://doi.org/10.1038/sj.leu.2402725

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