Novel role of STAT3 in NPM/ALK-induced oncogenesis

这项建议旨在更好地理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)和/或在人类T细胞和B细胞淋巴瘤的亚群中激活，炎症性 肌纤维母细胞瘤，非小细胞肺癌的亚型，横纹肌脊索瘤， 神经母细胞瘤、胶质母细胞瘤和视网膜母细胞瘤，显然还有其他恶性肿瘤。鉴于 NPM/ALK是高度致癌的，ALK介导的细胞转化的确切机制 仍然只有部分阐明。在这项研究中，我们将通过以下重点来检验这些机制 NPM/ALK激活的关键转录因子：STAT3和STAT5b STAT3在诱导表观遗传基因沉默中的作用。我们还将开发临床前模型 靶向治疗旨在同时干扰ALK/STAT介导的细胞信号和 ALK表达式。为实现这些目标，我们将： 1.鉴定受NPM/ALK-STAT3和NPM/ALK-STAT5b信号通路调控的基因 并检查由选定的已识别基因编码的蛋白质在恶性细胞中的作用 转型。 2.研究STAT3诱导的Stat5a基因表观遗传沉默的机制。 3.测定ALK和DNMT抑制剂在体内外对肿瘤生长的影响。 这项研究将有助于进一步阐明ALK驱动的肿瘤的发病机制和 可能为这些恶性疾病的新的、有针对性的治疗铺平道路。因为 STAT3和STAT5的异常激活与肿瘤的表观遗传沉默 在大量的恶性肿瘤中已经发现了抑制基因，其结果是 这项研究也可能对其他类型癌症的研究和治疗产生影响。

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.