Dysregulation of STAT3 in ALK-induced oncogenesis

描述(由申请人提供)：这项建议旨在了解由致癌间变性大细胞淋巴瘤激酶(ALK)介导的恶性转化机制，迄今已发现在人类T/零细胞淋巴瘤(ALK？TCL)、横纹肌肉肉瘤、神经母细胞瘤和炎性肌纤维母细胞瘤的亚群中表达。虽然ALK能够转化淋巴样细胞，但ALK介导的肿瘤发生机制大多仍不清楚。在这项研究中，我们将确定STAT3和STAT3调节和效应蛋白在ALK介导的肿瘤发生中的作用，并建立临床前模型，旨在开发基于靶向ALK/STAT相关细胞信号的ALK TCL的新治疗方法。为实现这一目标，我们将： 1检测ALK TC中STAT3激活的患病率和致癌后果。明确STAT3激活的负调控因子(PIAS3、SOCS3和SHIP-I)在ALK TCL发病机制中的作用，并探讨其表达和功能的调控机制。3利用基因芯片技术检测STAT3下游效应基因和潜在的新的STAT3靶基因在ALK TCL发病机制中的表达和功能。检测ALK抑制剂、STAT3反义寡核苷酸、mTOR激酶抑制剂、PP2A抑制剂和/或DNA甲基化抑制剂/SHP-1磷酸酶诱导剂对ALK TCL细胞体外和体内的影响。 这项研究将有助于更好地了解ALK TCL的发病机制，并可能导致基于选择性抑制ALK、STAT3和STAT3调节分子介导的细胞信号转导的此类淋巴瘤的新疗法。由于STAT3信号的异常在各种血液性和非血液性肿瘤的发病机制中起关键作用，而且ALK的异常表达并不局限于ALK？TCL，因此本研究的结果可能会对理解多种恶性肿瘤的发病机制和治疗产生影响。

DESCRIPTION (provided by the applicant): This proposal is aimed at understanding mechanisms of malignant transformation mediated by an oncogenic anaplastic large cell lymphoma kinase (ALK) found so far to be expressed in the subset of human T/null-cell lymphomas (ALK¿ TCL), rhabdomyosarcomas, neuroblastomas, and inflammatory myofibroblastic tumors. Whereas ALK is capable of transforming lymphoid cells, the mechanisms of ALK-mediated oncogenesis remain mostly unknown. In this study we will determine the role of STAT3 and STAT3 regulatory and effector proteins in the ALK-mediated oncogenesis and establish preclinical model aimed at development of novel treatment for ALK+ TCL based on targeting ALK/STAT-related cell signaling. To accomplish this goal we will: 1 examine the prevalence and oncogenic consequences of the STAT3 activation in ALK+ TCL.2. define the role of negative regulators of STAT3 activation (PIAS3, SOCS3, and SHIP-i) in the ALK+ TCL pathogenesis and explore the mechanisms that control their expression and function.3 identify and determine the role in ALK+ TCL pathogenesis of the down-stream effectors of STAT3 by examining the expression and function of genes known to be regulated by STAT3 and potential novel STAT3 target genes using cDNA microarray technology.4. determine the in vitro and in vivo effects on ALK+TCL cells of drug combinations that include ALK inhibitor, STAT3 antisense oligonucleotide, mTOR kinase inhibitor, PP2A inhibitor, and/or DNA methylation inhibitor/SHP- 1 phosphatase inducer. This study should result in a better understanding of the pathogenesis of ALK+ TCL and may lead to novel therapies for this type of lymphoma based on selective inhibition of the cell signaling mediated by ALK, STAT3 and STAT3-regulatory molecules different from ALK. Because aberrant STAT3 signaling emerges as a critical factor in the pathogenesis of various types of hematopoietic and non-hematopoietic tumors and aberrant ALK expression is not limited only to the ALK¿ TCL, results of this study may impact on understanding pathogenesis and treatment of broad spectrum of malignancies.