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Permanent link (DOI): https://doi.org/10.7939/R33439

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The Role of Oncogenic Tyrosine Kinase NPM-ALK in Anaplastic Large Cell Lymphoma Pathobiology Open Access

Descriptions

Other title
Subject/Keyword
ALCL
Tyrosine Kinase
NPM-ALK
Oncogenic
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Hegazy, Samar, A T
Supervisor and department
Lai, Raymond (Laboratory Medicine and Pathology)
Examining committee member and department
Ingham, Robert (Medical Microbiology and Immunology)
Shaw, Andrew (Oncology)
Martin, Jonathan (Laboratory Medicine and Pathology)
Robbins, Stephen (Departments of Oncology and Biochemistry & Molecular Biology-University of Calgary))
Leng, Roger (Laboratory Medicine and Pathology)
Department
Medical Sciences- Laboratory Medicine and Pathology
Specialization

Date accepted
2012-06-29T15:23:59Z
Graduation date
2012-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Anaplastic lymphoma kinase expressing anaplastic large cell lymphoma (ALK+ALCL) is an aggressive type of T/null cell lymphoma that mainly affects children and young adults and represents up to 40% of non-Hodgkin’s lymphoma in children. These lymphomas are characterized by the abnormal chromosomal translocations involving the ALK gene resulting in the aberrant expression of an oncogenic fusion protein with constitutive activation of the ALK tyrosine kinase domain. In up to 80% of ALK+ALCL cases, this fusion protein is nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK conducts its transforming ability through activation of many molecular mechanisms. Despite the well-known role of NPM-ALK in the pathogenesis of ALK+ALCL as demonstrated by several in vitro and in vivo studies, there is evidence argue that this protein does not act alone in these tumors. Further studies are required to identify additional molecular defects in ALK+ALCL, which could contribute to or potentiate NPM-ALK oncogenicity. The first objective of this thesis examined the detailed mechanism of interaction between NPM-ALK and the tumor suppressor protein tyrosine phosphatase SHP1, a protein normally absent in most of ALK+ALCL. Furthermore, the biological importance of this binding was demonstrated. The second objective examined the aberrant expression of the embryonic stem cells (ESCs) transcription factor Sox2 in ALK+ALCL cell lines and tumors. Despite its ubiquitous expression, Sox2 transcription activity was detected only in a small subset of tumor cells. Sox2 was demonstrated to contribute to ALK+ALCL tumorigenesis, and its oncogenic potential correlated with its transcriptional activity. The third objective examined the over-expression of the Wnt pathway members in ALK+ALCL. The over-expression of disheveled proteins 2 and 3 (Dvl-2 and Dvl-3), was detected in ALK+ALCL cell lines and tumors. I demonstrated that Dvl-2 and Dvl-3 play a significant biological role in ALK+ALCL, and signal through the Wnt non-canonical pathway. Furthermore, cross talk between NPM-ALK and Wnt pathway through Dvl proteins was identified. Overall, the identification of these novel signaling defects and their mechanisms in ALK+ALCL oncogenesis furthered our current understanding of the pathobiology of these tumors and provided a framework for the development of multi-target therapies for these malignancies.
Language
English
DOI
doi:10.7939/R33439
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Hegazy SA, Wang P, Anand M, Ingham RJ, Gelebart P, Lai R. The tyrosine343 residue of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is important for its interaction with SHP1, a cytoplasmic tyrosine phosphatase with tumor suppressor functions.J Biol Chem. 2010 Jun 25;285(26):19813-20

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