Essential role for the p110δ isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia
Essential role for the p110δ isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia
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DOI：
10.1182/blood-2004-08-3225
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发表时间：
2005-08-01
期刊：
影响因子：
20.3
通讯作者：
Bouscary, D
中科院分区：
文献类型：
--
作者：
Sujobert, P;Bardet, V;Bouscary, D
磷酸肌醇 3 激酶 (PI3K)/Akt 信号通路已被证明在急性髓性白血病 (AML) 患者的母细胞中经常被激活，并有助于这些细胞的存活和增殖。在 PI3K 的 8 种不同哺乳动物亚型中，I 类 PI3K（p110 α、p110 β、p110 γ 和 p110 δ）负责 Akt 激活。目前尚不清楚哪种 PI3K 同工型在 AML 中至关重要。在这里，我们发现 PI3K 的 p110 δ 异构体在 AML 的母细胞中始终保持高水平表达，而其他 I 类异构体则相反，后者的表达在患者中差异很大。 IC87114 是一种 p1110 δ 选择性抑制剂，可抑制原始细胞中的组成型和 Fit-3 刺激的 Akt 激活，其程度与所有 PI3K 同工型抑制剂 Ly294002 相同。此外，IC87114 抑制 AML 细胞增殖，而不影响正常造血祖细胞的增殖。这些观察结果表明 p1106 是 AML 的潜在治疗靶点。
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.