Abstract

: 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096856-02
Application #
6604201
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Mufson, R Allan
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$301,150
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Werner, Michael T; Zhang, Qian; Wasik, Mariusz A (2017) From Pathology to Precision Medicine in Anaplastic Large Cell Lymphoma Expressing Anaplastic Lymphoma Kinase (ALK+ ALCL). Cancers (Basel) 9:
Zhang, Qian; Wang, Hong Yi; Wei, Fang et al. (2014) Cutaneous T cell lymphoma expresses immunosuppressive CD80 (B7-1) cell surface protein in a STAT5-dependent manner. J Immunol 192:2913-9
Krejsgaard, Thorbjørn; Willerslev-Olsen, Andreas; Lindahl, Lise M et al. (2014) Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation. Blood 124:761-70
Zhang, Qian; Wei, Fang; Wang, Hong Yi et al. (2013) The potent oncogene NPM-ALK mediates malignant transformation of normal human CD4(+) T lymphocytes. Am J Pathol 183:1971-80
Marzec, Michal; Halasa, Krzysztof; Liu, Xiaobin et al. (2013) Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming. J Immunol 191:6200-7
Lee, Seung-Cheol; Marzec, Michal; Liu, Xiaobin et al. (2013) Decreased lactate concentration and glycolytic enzyme expression reflect inhibition of mTOR signal transduction pathway in B-cell lymphoma. NMR Biomed 26:106-14
Yao, Sheng; Cheng, Mangeng; Zhang, Qian et al. (2013) Anaplastic lymphoma kinase is required for neurogenesis in the developing central nervous system of zebrafish. PLoS One 8:e63757
Lee, Seung-Cheol; Arias-Mendoza, Fernando; Poptani, Harish et al. (2012) Prediction and Early Detection of Response by NMR Spectroscopy and Imaging. PET Clin 7:119-26
Zhang, Qian; Wang, Hongyi; Kantekure, Kanchan et al. (2011) Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS. Blood 118:3062-71
Marzec, M; Liu, X; Wong, W et al. (2011) Oncogenic kinase NPM/ALK induces expression of HIF1? mRNA. Oncogene 30:1372-8

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