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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
CD4-Positive T-Lymphocytes / metabolism
-
Cell Proliferation
-
Flow Cytometry
-
Genetic Therapy / methods*
-
Granulocyte-Macrophage Colony-Stimulating Factor
-
Humans
-
Infant, Newborn
-
Inositol Polyphosphate 5-Phosphatases
-
Intracellular Signaling Peptides and Proteins / genetics*
-
Leukemia, Myelomonocytic, Chronic / immunology
-
Leukemia, Myelomonocytic, Chronic / therapy*
-
Mutation
-
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
-
Phosphoric Monoester Hydrolases / genetics*
-
Protein Tyrosine Phosphatase, Non-Receptor Type 11
-
Protein Tyrosine Phosphatases / genetics*
-
Proto-Oncogene Proteins / genetics*
-
Proto-Oncogene Proteins p21(ras)
-
Transduction, Genetic / methods
-
ras Proteins / genetics*
Substances
-
Intracellular Signaling Peptides and Proteins
-
KRAS protein, human
-
Proto-Oncogene Proteins
-
Granulocyte-Macrophage Colony-Stimulating Factor
-
Phosphoric Monoester Hydrolases
-
PTPN11 protein, human
-
Protein Tyrosine Phosphatase, Non-Receptor Type 11
-
Protein Tyrosine Phosphatases
-
Inositol Polyphosphate 5-Phosphatases
-
INPP5D protein, human
-
Inpp5d protein, mouse
-
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
-
Proto-Oncogene Proteins p21(ras)
-
ras Proteins