Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, Rm 2338, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2.
Ther Adv Hematol. 2013 Apr;4(2):119-31. doi: 10.1177/2040620712471553.
Extensive research has been carried out in the past two decades to study the pathobiology of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which is an oncogenic fusion protein found exclusively in a specific type of T-cell lymphoid malignancy, namely ALK-positive anaplastic large cell lymphoma. Results from these studies have provided highly useful insights into the mechanisms by which a constitutively tyrosine kinase, such as NPM-ALK, promotes tumorigenesis. Several previous publications have comprehensively summarized the advances in this field. In this review, we provide readers with a brief update on specific areas of NPM-ALK pathobiology. In the first part, the NPM-ALK/signal transducer and activator of transcription 3 (STAT3) signaling axis is discussed, with an emphasis on the existence of multiple biochemical defects that have been shown to amplify the oncogenic effects of this signaling axis. Specifically, findings regarding JAK3, SHP1 and the stimulatory effects of several cytokines including interleukin (IL)-9, IL-21 and IL-22 are summarized. New concepts stemming from recent observations regarding the functional interactions among the NPM-ALK/STAT3 axis, β catenin and glycogen synthase kinase 3β will be postulated. Lastly, new mechanisms by which the NPM-ALK/STAT3 axis promotes tumorigenesis, such as its modulations of Twist1, hypoxia-induced factor 1α, CD274, will be described. In the second part, we summarize recent data generated by mass spectrometry studies of NPM-ALK, and use MSH2 and heat shock proteins as examples to illustrate the use of mass spectrometry data in stimulating new research in this field. In the third part, the evolving field of microRNA in the context of NPM-ALK biology is discussed.
在过去的二十年中，人们进行了广泛的研究来探究核磷蛋白-间变性淋巴瘤激酶（NPM-ALK）的病理生物学，它是一种致癌融合蛋白，仅存在于一种特定类型的 T 细胞淋巴恶性肿瘤中，即 ALK 阳性间变性大细胞淋巴瘤。这些研究的结果为了解组成性酪氨酸激酶（如 NPM-ALK）促进肿瘤发生的机制提供了非常有用的见解。以前的几篇出版物已经全面总结了该领域的进展。在这篇综述中，我们为读者提供了 NPM-ALK 病理生物学特定领域的简要更新。在第一部分中，讨论了 NPM-ALK/信号转导子和转录激活子 3（STAT3）信号轴，重点介绍了已经证明可放大该信号轴致癌作用的多种生化缺陷。具体而言，总结了关于 JAK3、SHP1 和几种细胞因子（包括白细胞介素（IL）-9、IL-21 和 IL-22）的刺激作用的发现。将提出源于最近关于 NPM-ALK/STAT3 轴、β 连环蛋白和糖原合成酶激酶 3β 之间功能相互作用的观察结果的新概念。最后，将描述 NPM-ALK/STAT3 轴促进肿瘤发生的新机制，例如其对 Twist1、缺氧诱导因子 1α、CD274 的调节。在第二部分中，我们总结了 NPM-ALK 的质谱研究产生的最新数据，并以 MSH2 和热休克蛋白为例来说明质谱数据在激发该领域新研究方面的应用。在第三部分中，讨论了 NPM-ALK 生物学中 microRNA 的不断发展的领域。
