Essential role for the p110δ isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia

被引:218
作者
Sujobert, P
Bardet, V
Cornillet-Lefebvre, P
Hayflick, JS
Prie, N
Verdier, F
Vanhaesebroeck, B
Muller, O
Pesce, F
Ifrah, N
Hunault-Berger, M
Berthou, C
Villemagne, B
Jourdan, E
Audhuy, B
Solary, E
Witz, B
Harousseau, JL
Himberlin, C
Lamy, T
Lioure, B
Cahn, JY
Dreyfus, F
Mayeux, P
Lacombe, C
Bouscary, D
机构
[1] Hop Cochin, Serv Hematol, AP HP, F-75014 Paris, France
[2] Hop Cochin, Dept Stat, F-75014 Paris, France
[3] Univ Paris 05, Inst Cochin Genet Mol, UMR 8104, CNRS,INSERM,Dept Hematol, Paris, France
[4] Hop Reims, Hematol Lab, Reims, France
[5] ICOS Corp, Bothell, WA USA
[6] UCL, Ludwig Inst Canc Res, London, England
[7] UCL, Dept Biochem & Mol Biol, London, England
[8] GOELAMS, Tours, France
关键词
D O I
10.1182/blood-2004-08-3225
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The phosphoinositicle 3-kinase (PI3K)/Akt signaling pathway has been shown to be frequently activated in blast cells from patients with acute myelold leukemia (AML) and to contribute to survival and proliferation of these cells. Of the 8 distinct mammalian isoforms of PI3K, it is the class I PI3Ks (p110 alpha, p110 beta, p110 gamma, and p110 delta) that are responsible for Akt activation. It is not known which PI3K isoform is critical in AML. Here we show that the p110 delta isoform of PI3K is consistently expressed at a high level in blast cells from AML, in contrast to the other class I isoforms, the expression of which was very variable among patients. IC87114, a p1110 delta-selective inhibitor, suppressed both constitutive and Fit-3-stimulated Akt activation in blasts to the same extent as Ly294002, an inhibitor of all PI3K isoforms. Moreover, IC87114 inhibited AML cell proliferation without affecting the proliferation of normal hematopoietic progenitor cells. These observations identify p1106 as a potential therapeutic target in AML.
引用
收藏
页码:1063 / 1066
页数:4
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