Dysregulation of STAT3 in ALK-induced oncogenesis

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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.