Reduced proliferation of [CD34.sup.+] 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...

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Bibliographic Details
Published inGene therapy Vol. 16; no. 4; pp. 570 - 573
Main Authors Metzner, A, Precht, C, Fehse, B, Fiedler, W, Stocking, C, Gunther, A, Mayr, G.W, Jucker, M
Format Journal Article
LanguageEnglish
Published Nature Publishing Group 01.04.2009
Subjects
Cell proliferation
Gene therapy
Genetic aspects
Health aspects
Germany
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Summary: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.sup.+] 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.sup.+] cells from a patient with a secondary AML who had a very high peripheral blast count (300 x [10.sup.9] [l.sup.-1]). These data show that SHIP1 can effectively block GM-CSF-dependent and autonomous proliferation of AML cells. doi:10.1038/gt.2008.184; published online 15 January 2009 Keywords: acute myeloid leukemia; SHIP1; inositol 5-phosphatase
ISSN:0969-7128
1476-5462