Novel role of STAT3 in NPM/ALK-induced oncogenesis

这一建议旨在更好地了解间变性大细胞的致癌作用， 淋巴瘤激酶（ALK）。ALK异常表达（最常见的是NPM/ALK融合蛋白 蛋白）和/或在人T细胞和B细胞淋巴瘤的亚群中活化，炎性 肌纤维母细胞肿瘤、非小细胞肺癌子集、横纹肌肉瘤， 神经母细胞瘤、胶质母细胞瘤和视网膜母细胞瘤，以及显然的其他恶性肿瘤。而 NPM/ALK是高度致癌的，ALK介导的细胞转化的确切机制是 仍然只是部分阐明。在这项研究中，我们将通过关注以下方面来研究这些机制： NPM/ALK激活的关键转录因子：STAT 3和STAT 5 b，包括 STAT 3诱导表观遗传基因沉默。我们还将开发临床前模型， 靶向治疗旨在同时破坏ALK/STAT介导的细胞信号传导， ALK表达。为了实现这些目标，我们将： 1.鉴定NPM/ALK-STAT 3和NPM/ALK-STAT 5 b信号通路调控的基因 并检查由所选的已鉴定基因编码的蛋白质在恶性细胞中的作用 转型 2.研究STAT 3诱导的STAT 5a基因表观遗传沉默的机制。 3.确定ALK和DNMT抑制剂对体外和体内肿瘤生长的影响。 本研究应进一步阐明ALK驱动肿瘤的发病机制， 可能为这些恶性疾病的新型靶向治疗铺平道路。因为 STAT 3和STAT 5的异常激活以及肿瘤的表观遗传沉默 抑制基因已被确定在大范围的恶性肿瘤，这一结果 这项研究也可能对其他类型癌症的研究和前瞻性治疗产生影响。

This proposal is aimed at a better understanding of the oncogenic role of anaplastic large cell lymphoma kinase (ALK). ALK is aberrantly expressed (most frequently as the NPM/ALK fusion protein) and/or activated in a subset of human T-cell and B-cell lymphomas, inflammatory myofibroblastic tumors, subsets of non-small cell lung carcinoma, rhabdomyosacroma, neuroblastoma, glioblastoma and retinoblastoma and, apparently, other malignancies. Whereas NPM/ALK is highly oncogenic, the exact mechanisms of the ALK-mediated cell transformation remain only partially elucidated. In this study we will examine these mechanisms by focusing on the key transcription factors activated by NPM/ALK: STAT3 and STAT5b including the role of STAT3 in induction of epigenetic gene silencing. We will also develop preclinical model of targeted therapy aimed at simultaneous disruption of the ALK/STAT-mediated cell signaling and ALK expression. To accomplish these goals we will: 1. Identify the genes regulated by NPM/ALK-STAT3 and NPM/ALK-STAT5b signaling pathways and examine the role of proteins encoded by the selected identified genes in the malignant cell transformation. 2. Examine the mechanisms of the STAT3-induced epigenetic silencing of the STAT5a gene. 3. Determine the effects of ALK and DNMT inhibitors on tumor growth in vitro and in vivo. This study should lead to further elucidation of pathogenesis of the ALK-driven neoplasms and may pave the road to novel, targeted therapies for these malignant disorders. Because the aberrant activation of STAT3 and STAT5 as well as the epigenetic silencing of tumor suppressor genes have been identified in the large spectrum of malignancies, results of this study may also have an impact on research and, prospectively, therapy of other types of cancer.