Gene transfer of SHIP-1 inhibits proliferation of juvenile myelomonocytic leukemia cells carrying KRAS2 or PTPN11 mutations.
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.
Metzner
A
A
University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I, Cellular Signal Transduction, Hamburg, Germany.
Horstmann
M A
MA
Fehse
B
B
Ortmeyer
G
G
Niemeyer
C M
CM
Stocking
C
C
Mayr
G W
GW
Jücker
M
M
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D007231:Infant, Newborn; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015477:Leukemia, Myelomonocytic, Chronic / Q000276:immunology / Q000628:therapy*; D009154:Mutation; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D014161:Transduction, Genetic / Q000379:methods; D018631:ras Proteins / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010744:Phosphoric Monoester Hydrolases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins