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

  • Author / Creator
    Hegazy, Samar, A T
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Medical Sciences- Laboratory Medicine and Pathology
  • Supervisor / co-supervisor and their department(s)
    • Lai, Raymond (Laboratory Medicine and Pathology)
  • Examining committee members and their departments
    • Leng, Roger (Laboratory Medicine and Pathology)
    • Robbins, Stephen (Departments of Oncology and Biochemistry & Molecular Biology-University of Calgary))
    • Martin, Jonathan (Laboratory Medicine and Pathology)
    • Shaw, Andrew (Oncology)
    • Ingham, Robert (Medical Microbiology and Immunology)