Gene transfer of SHIP-1 inhibits proliferation of juvenile myelomonocytic leukemia cells carrying KRAS2 or PTPN11 mutations

Abstract

Juvenile myelomonocytic leukemia (JMML) is a malignant disease of early childhood characterized by a hypersensitivity to granulocyte/macrophage colony-stimulating factor (GM-CSF). Mutations in RAS or PTPN11 are frequently detected in JMML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP-1) is a negative regulator of GM-CSF signaling, and inactivation of SHIP-1 in mice results in a myeloproliferative disease. Here, we report the effects of SHIP-1 expression on GM-CSF-dependent proliferation and colony formation of human hematopoietic cells. After retroviral-mediated transduction of SHIP-1 into CD34 + cells from cord blood of healthy newborns or peripheral blood of JMML patients carrying mutations in KRAS2 or PTPN11, we observed a reduction in GM-CSF-dependent proliferation and colony formation. An enzymatically inactive form of SHIP-1 (D672A) had no effect. These data indicate that SHIP-1 can effectively block GM-CSF hypersensitivity in JMML progenitor cells with mutations in KRAS2 or PTPN11 and may be a useful approach for the treatment of JMML patients.

Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging

“…SHIP-1-deficient mice develop a myeloproliferative disease [138] and an inactivating point mutation ( SHIP V684E ) has been observed in approximately one of thirty AML cases [137]. Also another mutation, SHIP Q1154L , has been observed in AML, but was even less frequent (1 of 192 cases) [138].…”

“…SHIP-1-deficient mice develop a myeloproliferative disease [138] and an inactivating point mutation ( SHIP V684E ) has been observed in approximately one of thirty AML cases [137]. Also another mutation, SHIP Q1154L , has been observed in AML, but was even less frequent (1 of 192 cases) [138]. Though some studies confirmed, that SHIP-1 is a leukemia suppressor [137, 138] it is unlikely that SHIP1 mutations are a frequent cause of Akt-activation in AML.…”

Reduced proliferation of CD34+ cells from patients with acute myeloid leukemia after gene transfer of INPP5D

“…Human SHIP1 cDNA and an enzymatic inactive SHIP1 mutant (D672A) 5,6 were cloned in the lentiviral vector pRRL.PPT.CMV.GFPpre. 293T cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum and 2 mM glutamine.…”

“…5 Gene transfer of INPP5D in CD34 + cells from patients with juvenile myeloid leukemia carrying mutations in KRAS2 or PTPN11 reduced their hypersensitivity for granulocyte macrophage-colony stimulating factor (GM-CSF). 6 In this report, we characterized the inhibitory effects of SHIP1 on the GM-CSF-dependent and autonomous proliferation of CD34 + cells from AML patients.…”

The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies

“…[10][11][12] Furthermore, we have demonstrated that overexpression of SHIP1 in primary leukemia cells from patients suffering from juvenile myelomonocytic leukemia or AML reduces the proliferation of the leukemia cells in vitro. 13,14 In addition, it has been shown that accompanying deletion of PTEN and SHIP1 causes development of lethal B cell lymphomas in mice. 15 These data strongly point to a tumor suppressor function of SHIP1 in haematopoietic cells.…”