1. ¹Department of Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan
2. ²Department of Genetic Diagnosis, Gifu International Institute of Biotechnology, Mitake, Japan
3. ³Institute of Applied Biochemistry, Mitake, Japan
4. ⁴Second Department of Internal Medicine, Nagoya City University Medical School, Nagoya, Japan
5. ⁵Department of Infectious Diseases, School of Medicine, Nagoya University, Nagoya, Japan
6. ⁶Aichi Cancer Center Hospital, Nagoya, Japan

Correspondence: H Yoshida, Department of Genetic Diagnosis, Gifu International Institute of Biotechnology, Yagi Memorial Park, Mitake, Gifu 505-0116, Japan; Fax: +81-574-67-6627

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

Received 29 April 2002; Accepted 2 July 2002.

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.