Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma
Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma
复制标题
DOI：
10.1182/blood-2006-04-015586
复制
发表时间：
2006-09-01
期刊：
影响因子：
20.3
通讯作者：
Raffeld, Mark
中科院分区：
文献类型：
--
作者：
Rudelius, Martina;Pittaluga, Stefania;Raffeld, Mark
为了确定PI 3 K/Akt信号通路是否参与套细胞淋巴瘤（MCL）的发病机制，我们研究了原发性MCL病例和细胞系中Akt和多个下游靶点的磷酸化状态。Akt在12/12个侵袭性胚MCL变体和4/4个MCL细胞系中磷酸化。相比之下，磷酸化Akt仅存在于16例典型MCL中的5例，3例与类胚细胞病例的水平相当，2例处于低水平。p-Akt的存在伴随着p27（kip 1）、FRKHL-1、MDM 2、Bad、mTOR和p70 S6 K的磷酸化。在MCL细胞系中抑制PI 3 K/Akt通路消除或减少Akt、p27（kip 1）、FRKHL-1、MDM 2、Bad、mTOR、GSK-3 β、I κ B的磷酸化，并导致细胞周期停滞和凋亡。6例MCL（5例Akt活化，1例Akt失活）和3/4株细胞系显示PTEN表达缺失。未检测到PIK 3CA突变。我们的结论是PI 3 K/Akt通路的组成性激活有助于MCL的发病机制，并优先发生在类胚变体。一种可能的激活机制是PTEN表达的丧失。这些数据表明，PI 3 K/Akt抑制剂可有效治疗Akt激活的MCL。
To determine whether the PI3K/Akt signaling pathway is involved in the pathogenesis of mantle cell lymphoma (MCL), we investigated the phosphorylation status of Akt and multiple downstream targets in primary MCL cases and cell lines. Akt was phosphorylated in 12 of 12 aggressive blastold MCL variants and in 4 of 4 MCL cell lines. In contrast, phosphorylated Akt was present in only 5 of 16 typical MCL, 3 at comparable levels to the blastoid cases, and 2 at low levels. The presence of p-Akt was accompanied by the phosphorylation of p27(kip1), FRKHL-1, MDM2, Bad, mTOR, and p70S6K. Inhibition of the PI3K/Akt pathway in the MCL cell lines abrogated or reduced the phosphorylation of Akt, p27(kip1), FRKHL-1, MDM2, Bad, mTOR, GSK-3 beta, I kappa B, and led to cell-cycle arrest and apoptosis. Six MCL cases (5 with activated Akt and 1 with inactive Akt) and 3 of 4 cell lines showed loss of PTEN expression. PIK3CA mutations were not detected. We conclude that constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis of MCL and preferentially occurs in blastoid variants. One possible mechanism of activation is loss of PTEN expression. These data suggest that PI3K/Akt inhibitors may be effective in the treatment of Akt-activated MCL.