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Understanding the function of the JunB transcription factor in anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma

  • Author / Creator
    Pearson, Joel Dylan
  • Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) is a non-Hodgkin lymphoma thought to arise from an activated T lymphocyte. This lymphoma is characterized by the presence of chromosomal translocations involving the ALK tyrosine kinase, which generate oncogenic fusion proteins, most commonly nucleophosmin (NPM)-ALK. NPM-ALK activates many signalling pathways that drive the proliferation, survival and migration of ALK+ ALCL cells. One of the downstream effectors of NPM-ALK signalling is the activator protein-1 family transcription factor, JunB. JunB is highly expressed in ALK+ ALCL and was reported to promote proliferation of ALK+ ALCL cell lines. Despite this, transcriptional targets of JunB that are important in the pathogenesis of ALK+ ALCL were largely uncharacterized. To better understand the function of JunB in ALK+ ALCL, we performed a quantitative mass spectrometry screen to identify JunB-regulated proteins in ALK+ ALCL cell lines. We identified the serine protease, Granzyme B (GzB), and the heat shock protein-90 co-chaperone, Cyclophilin 40 (Cyp40), as potential JunB-regulated proteins in ALK+ ALCL. Here, we demonstrate that GzB and Cyp40 are JunB transcriptional targets, and that NPM-ALK and JunB signalling promotes GzB and Cyp40 expression in ALK+ ALCL. By regulating the expression of GzB and the related protein, Perforin, we show that NPM-ALK and JunB influence the cytotoxic phenotype observed in ALK+ ALCL. Since the expression of GzB and Cyp40 was promoted by oncogenic signalling in ALK+ ALCL, we examined whether they play important roles in the pathogenesis of this lymphoma. Interestingly, we found that GzB expression actually sensitized ALK+ ALCL cell lines to apoptosis following treatment with apoptosis-inducing drugs. This finding is consistent with the observation that ALK+ ALCL patients are often successfully treated using standard chemotherapy regimens. We further found that Cyp40 promoted the viability of ALK+ ALCL cell lines. Together, our results shed light onto the function of an important transcription factor in ALK+ ALCL, and demonstrate that JunB regulates the expression of genes that contribute to multiple aspects of ALK+ ALCL biology. Furthermore, our findings uncover novel signalling events downstream of the NPM-ALK oncoprotein, and better clarify the molecular mechanisms underlying ALK+ ALCL phenotype and pathogenesis.

  • Subjects / Keywords
  • Graduation date
    2013-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3N697
  • 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
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Medical Microbiology and Immunology
  • Specialization
    • Immunology
  • Supervisor / co-supervisor and their department(s)
    • Ingham, Robert (Medical Microbiology and Immunology)
  • Examining committee members and their departments
    • Berthiaume, Luc (Cell Biology)
    • Harder Kenneth (Microbiology and Immunology, UBC)
    • Barry, Michele (Medical Microbiology and Immunology)
    • Baldwin, Troy (Medical Microbiology and Immunology)