Dysregulation of STAT3 in ALK-induced oncogenesis

描述（由申请人提供）：该提案旨在了解由一种致癌间变性大细胞淋巴瘤激酶（ALK）介导的恶性转化机制，目前发现该激酶在人T/零细胞淋巴瘤（ALK¿TCL）、横纹肌肉瘤、神经母细胞瘤和炎症性肌纤维母细胞肿瘤亚群中表达。虽然ALK能够转化淋巴样细胞，但ALK介导的肿瘤发生机制仍不清楚。在本研究中，我们将确定STAT3和STAT3调控蛋白和效应蛋白在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ALK/ stat相关细胞信号传导的ALK+ TCL的新治疗方法。为实现这一目标，我们将：

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.