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

Abstract

The SH2 domain-containing inositol 5Ј-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 5Ј-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.

A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells

“…57 SHIP is a hematopoietic-specific inhibitory phosphatase, 58 which dephosphorylates PtdIns(3,4,5)P 3 to PtdIns(3,4)P 2 (59). It is of great interest that in SHIPÀ/À mast cells Akt was more active.…”

Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias

“…In our study, SHIP was expressed in all AML samples studied. However, a dominant-negative mutation of SHIP with the loss of the catalytic activity was recently described in 1/30 primary AML samples, 63 suggesting a possible tumor suppressor role of SHIP in selected AML cases. Furthermore, mutations in PTEN were described in a limited number of AML cases studied.…”

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

“…SHIP mutations are also detected in AML. 273,274 In summary, the PTEN and SHIP phosphatases play critical roles in leukemogenesis. We are only beginning to understand how these proteins function to regulate growth in normal hematopoietic stem cells and as we learn more about their pleiotropic effects, we may be able to understand their contributions to leukemic stem cells and be able to counteraffect the consequences of mutations that inactivate these proteins.…”