Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia.
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.
Luo
J-M
JM
Department of Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Yoshida
H
H
Komura
S
S
Ohishi
N
N
Pan
L
L
Shigeno
K
K
Hanamura
I
I
Miura
K
K
Iida
S
S
Ueda
R
R
Naoe
T
T
Akao
Y
Y
Ohno
R
R
Ohnishi
K
K
D000208:Acute Disease; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D007377:Interleukin-3 / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D014162:Transfection; D014407:Tumor Cells, Cultured; D018909:src Homology Domains / Q000235:genetics
D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D007377:Interleukin-3; D019869:Phosphatidylinositol 3-Kinases; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human