Signal Transduction in Lymphoma

间变性大细胞淋巴瘤（ALCL）在普通人群中约占非霍奇金淋巴瘤的8%，在人类免疫缺陷病毒（HIV）感染患者中占25%。所有ALCL均表达肿瘤坏死因子（TNF）受体家族成员CD30。在非hiv人群中，超过60%的ALCL病例是由蛋白酪氨酸激酶间变性淋巴瘤激酶（ALK）激活引起的。ALK通常由2:5染色体易位激活，产生与核磷蛋白（NPM）的融合，称为NPM-ALK。对于NPM-ALK激活的信号转导途径以及它是如何引起淋巴瘤的，我们知之甚少。ALCL是独特的，因为CD30刺激抑制细胞生长。尽管针对CD30的抗体被用作治疗手段，但它们阻止细胞生长的机制尚不清楚。我们的目标是建立NPM-ALK引起淋巴瘤所需的信号通路的基础知识，并通过CD30刺激抑制ALCL的生长来描绘该通路。磷酸肌肽3-激酶（PI3K）是转录的信号转换器和激活因子（STAT） 5和磷脂酶C γ，由NPM-ALK激活。我们的研究表明，NPM-ALK使支架蛋白Gab2和IRS-1磷酸化，从而激活PI 3-激酶，可能还激活STAT 3和STAT 5。我们将确定NPM-ALK激活PI3K和STAT蛋白的途径，以及这些途径在淋巴瘤发生中的重要性。我们将使用生物化学和遗传方法来回答这些问题。我们的研究表明，CD30通过抑制PI3K和诱导细胞周期蛋白依赖性激酶抑制剂p21waf1而导致生长停滞。主要使用生化方法，我们将建立CD30激活阻止ALCL细胞生长的信号通路。这些研究的结果应该为ALCL如何发展以及CD30刺激如何作为治疗方法提供重要的见解。这一知识也可能有助于开发其他CD30阳性淋巴瘤的治疗方法，并了解其他致癌基因如何导致癌症。

Anaplastic large cell lymphoma (ALCL) constitutes about 8 percent of non-Hodgkin's lymphomas in the general population and 25 percent in patients with human immunodeficiency virus (HIV) infection. All ALCL express the tumor necrosis factor (TNF) receptor family member CD30. More than 60 percent of the cases of ALCL in the non-HIV population are caused by activation of the protein tyrosine kinase anaplastic lymphoma kinase (ALK). ALK is usually activated by a 2:5 chromosomal translocation that produces a fusion with nucleophosmin (NPM), called NPM-ALK. Very little is known about the signal transduction pathways activated by NPM-ALK and thus, how it causes lymphoma. ALCL is unique because CD30 stimulation arrests cell growth. Although antibodies to CD30 are being used as therapy, the mechanism by which they arrest cell growth is not known. Our goals are to develop a foundation of knowledge about the signaling pathways necessary for NPM-ALK to cause lymphoma and to delineate the pathway by with CD30 stimulation arrests growth in ALCL. Phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription (STAT) 5 and phospholipase C gamma, are activated by NPM-ALK. Our studies suggest NPM-ALK phosphorylates the scaffolding proteins Gab2 and IRS-1 and thereby activates PI 3-kinase and probably STAT 3 and 5. We will determine the pathways by which NPM-ALK activates PI3K and STAT proteins and the importance of these pathways for lymphomagenesis. We will use both biochemical and genetic approaches to answer these questions. Our studies indicate that CD30 causes growth arrest as a result of inhibition of PI3K and induction of the cyclin- dependent kinase inhibitor, p21waf1. Using primarily a biochemical approach, we will establish the signaling pathway by which CD30 activation arrests cell growth in ALCL. The results of these studies should provide critical insights into how ALCL develops and how CD30 stimulation works as therapy. This knowledge may also help in developing treatment for other CD30 positive lymphomas and understanding how other oncogenes cause cancer.