Reduced proliferation of CD34(+) cells from patients with acute myeloid leukemia after gene transfer of INPP5D.
Acute myeloid leukemia (AML) is a malignant disease characterized by deregulated proliferation of immature myeloid cells. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently detected in approximately 50-70% of AML patients. The gene INPP5D encodes the SH2-containing inositol 5-phosphatase 1 (SHIP1), which is a negative regulator of PI3K/AKT signaling. After lentiviral-mediated gene transfer of INPP5D into CD34(+) cells derived from AML patients (n=12) the granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent proliferation was reduced in all samples analyzed (average 86%; range 72-93%). An enzymatically inactive form of SHIP1 (D672A) had no effect. In addition, SHIP1 reduced the autonomous proliferation of CD34(+) cells from a patient with a secondary AML who had a very high peripheral blast count (300 x 10(9) l(-1)). These data show that SHIP1 can effectively block GM-CSF-dependent and autonomous proliferation of AML cells.
Metzner
A
A
Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I, Cellular Signal Transduction, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Precht
C
C
Fehse
B
B
Fiedler
W
W
Stocking
C
C
Günther
A
A
Mayr
G W
GW
Jücker
M
M
D018952:Antigens, CD34 / Q000097:blood*; D049109:Cell Proliferation / Q000187:drug effects; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D016086:Lentivirus / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000473:pathology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D012263:Ribonucleosides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D012263:Ribonucleosides; C023764:triciribine; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases