Signal Transduction in Lymphoma

淋巴瘤的信号转导

• 批准号: 7072304
• 负责人: CHRISTOPHER CARPENTER
• 金额: $ 29.55万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072304
• 关键词: biological models; biological signal transduction; bone marrow transplantation; carcinogenesis; cell growth regulation; cell line; cytokine receptors; enzyme activity; enzyme mechanism; gel mobility shift assay; genetic transcription; human genetic material tag; immunoprecipitation; laboratory mouse; molecular oncology; neoplasm /cancer genetics; neoplasm /cancer immunology; nonHodgkin' s lymphoma; phosphatidylinositol 3 kinase; posttranslational modifications; protein protein interaction; protein tyrosine kinase; tumor necrosis factor alpha; western blottings

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.

间变性大细胞淋巴瘤 (ALCL) 约占普通人群非霍奇金淋巴瘤的 8%，占人类免疫缺陷病毒 (HIV) 感染患者的 25%。 所有 ALCL 均表达肿瘤坏死因子 (TNF) 受体家族成员 CD30。 非 HIV 人群中 60% 以上的 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。 人们对 NPM-ALK 激活的信号转导途径以及它如何导致淋巴瘤知之甚少。 ALCL 是独特的，因为 CD30 刺激会阻止细胞生长。 尽管 CD30 抗体被用作治疗方法，但它们阻止细胞生长的机制尚不清楚。 我们的目标是建立有关 NPM-ALK 引起淋巴瘤所需信号通路的基础知识，并通过 CD30 刺激阻止 ALCL 的生长来描绘该通路。磷酸肌醇 3-激酶 (PI3K)、信号转导子和转录激活子 (STAT) 5 以及磷脂酶 C γ 由 NPM-ALK 激活。 我们的研究表明，NPM-ALK 磷酸化支架蛋白 Gab2 和 IRS-1，从而激活 PI 3 激酶，可能还激活 STAT 3 和 5。我们将确定 NPM-ALK 激活 PI3K 和 STAT 蛋白的途径以及这些途径对淋巴瘤发生的重要性。 我们将使用生化和遗传学方法来回答这些问题。 我们的研究表明，CD30 由于抑制 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。 我们将主要使用生化方法，建立 CD30 激活阻止 ALCL 细胞生长的信号传导途径。 这些研究的结果应该为 ALCL 如何发展以及 CD30 刺激如何作为治疗发挥作用提供重要见解。 这些知识还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癌基因如何导致癌症。