Prabhu S, Saadat D, Zhang M, Halbur L, Fruehauf J P, Ong S T
The Division of Hematology/Oncology, University of California, Irvine, CA 92697, USA.
Oncogene. 2007 Feb 22;26(8):1188-200. doi: 10.1038/sj.onc.1209901. Epub 2006 Aug 28.
The oncogenic kinase Bcr-Abl is thought to cause chronic myelogenous leukemia (CML) by altering the transcription of specific genes with growth- and survival-promoting functions. Recently, Bcr-Abl has also been shown to activate an important regulator of protein synthesis, the mammalian target of rapamycin (mTOR), which suggests that dysregulated translation may also contribute to CML pathogenesis. In this study, we found that both Bcr-Abl and the rapamycin-sensitive mTORC1 complex contribute to the phosphorylation (inactivation) of 4E-BP1, an inhibitor of the eIF4E translation initiation factor. Experiments with rapamycin and the Bcr-Abl inhibitor, imatinib mesylate, in Bcr-Abl-expressing cell lines and primary CML cells indicated that Bcr-Abl and mTORC1 induced formation of the translation initiation complex, eIF4F. This was characterized by reduced 4E-BP1 binding and increased eIF4G binding to eIF4E, two events that lead to the assembly of eIF4F. One target transcript is cyclin D3, which is regulated in Bcr-Abl-expressing cells by both Bcr-Abl and mTORC1 in a translational manner. In addition, the combination of imatinib and rapamycin was found to act synergistically against committed CML progenitors from chronic and blast phase patients. These experiments establish a novel mechanism of action for Bcr-Abl, and they provide insights into the modes of action of imatinib mesylate and rapamycin in treatment of CML. They also suggest that aberrant cap-dependent mRNA translation may be a therapeutic target in Bcr-Abl-driven malignancies.
致癌激酶Bcr-Abl被认为通过改变具有促进生长和存活功能的特定基因的转录来引发慢性粒细胞白血病（CML）。最近，Bcr-Abl还被证明可激活蛋白质合成的一个重要调节因子——雷帕霉素哺乳动物靶标（mTOR），这表明翻译失调也可能促成CML的发病机制。在本研究中，我们发现Bcr-Abl和对雷帕霉素敏感的mTORC1复合物都促成了4E-BP1（eIF4E翻译起始因子的一种抑制剂）的磷酸化（失活）。在表达Bcr-Abl的细胞系和原发性CML细胞中使用雷帕霉素和Bcr-Abl抑制剂甲磺酸伊马替尼进行的实验表明，Bcr-Abl和mTORC1诱导了翻译起始复合物eIF4F的形成。其特征是4E-BP1结合减少以及eIF4G与eIF4E的结合增加，这两个事件导致了eIF4F的组装。一个靶转录本是细胞周期蛋白D3，它在表达Bcr-Abl的细胞中受到Bcr-Abl和mTORC1的翻译调控。此外，发现甲磺酸伊马替尼和雷帕霉素联合使用对慢性期和急变期患者的定向CML祖细胞具有协同作用。这些实验确立了Bcr-Abl的一种新作用机制，并为甲磺酸伊马替尼和雷帕霉素在CML治疗中的作用方式提供了见解。它们还表明，异常的帽依赖性mRNA翻译可能是Bcr-Abl驱动的恶性肿瘤的一个治疗靶点。
