Syk-dependent mTOR activation in follicular lymphoma cells
Syk-dependent mTOR activation in follicular lymphoma cells
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DOI：
10.1182/blood-2006-05-026203
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发表时间：
2006-12-15
期刊：
影响因子：
20.3
通讯作者：
Bezombes, Christine
中科院分区：
文献类型：
--
作者：
Leseux, Ludivine;Hamdi, Safouane M.;Bezombes, Christine
哺乳动物雷帕霉素靶蛋白（mTOR）是一个很有前途的抗肿瘤治疗靶点。然而，在B淋巴瘤中促进其调节的机制仍然未知。这项研究表明，在滤泡性淋巴瘤（FL）细胞中，mTOR是活跃的，因为细胞显示雷帕霉素敏感的p70S6激酶和4E-BP1磷酸化。此外，免疫组化应用于从FL患者的淋巴结组织切片显示，在大多数情况下，p70S6激酶是高度磷酸化相比，正常扁桃体组织。在FL细胞中，mTOR受磷脂酶D（PLD）和磷脂酰肌醇3-激酶（PI3K）的控制。此外，我们证明Syk在mTOR激活中起核心作用，因为我们发现与正常或慢性淋巴细胞白血病B细胞相比，Syk的表达和活性都升高。我们还提供了证据表明，Syk通过PLD和PI3K独立途径运作。最后，Syk抑制piceatannol或siRNA质粒导致在FL细胞，以及套细胞淋巴瘤，伯基特淋巴瘤，弥漫性大B细胞淋巴瘤的mTOR活性的有效抑制。这些发现表明Syk-mTOR通路在FL存活中具有关键功能，因此，Syk可能是B淋巴瘤治疗的有希望的新靶点。（血。2006; 108：4156 - 4162）（c）2006年由美国血液学学会。
The mammalian target of rapamycin (mTOR) is emerging as a promising target for antitumor therapy. However, the mechanism that contributes to its regulation in B lymphomas remains unknown. This study shows that in follicular lymphoma (FL) cells, mTOR is active because the cells displayed rapamycin-sensitive phosphorylation of p70S6 kinase and 4E-BP1. Moreover, immunohistochemistry applied on lymph node tissue sections obtained from patients with FL revealed that, in most cases, p70S6 kinase was highly phosphorylated compared to normal tonsillar tissue. In FL cells, mTOR was under control of both phospholipase D (PLD) and phosphatidylinositol 3-kinase (PI3K). Moreover, we demonstrated that Syk plays a central role in mTOR activation because we found that both expression and activity are elevated compared to normal or chronic lymphocytic leukemia B cells. We also provide evidence that Syk operates through PLD- and PI3K-independent pathways. Finally, Syk inhibition by piceatannol or by siRNA plasmids resulted in a potent inhibition of mTOR activity in FL cells, as well as in mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma. These findings suggest that the Syk-mTOR pathway has a critical function in FL survival, and therefore, that Syk could be a promising new target for B-lymphoma therapy. (Blood. 2006; 108:4156-4162)(c) 2006 by The American Society of Hematology.