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Permanent link (DOI): https://doi.org/10.7939/R3N697
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Understanding the function of the JunB transcription factor in anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma Open Access
- Other title
- Type of item
- Degree grantor
University of Alberta
- Author or creator
Pearson, Joel Dylan
- Supervisor and department
Ingham, Robert (Medical Microbiology and Immunology)
- Examining committee member and department
Berthiaume, Luc (Cell Biology)
Barry, Michele (Medical Microbiology and Immunology)
Baldwin, Troy (Medical Microbiology and Immunology)
Harder Kenneth (Microbiology and Immunology, UBC)
Department of Medical Microbiology and Immunology
- Date accepted
- Graduation date
Doctor of Philosophy
- Degree level
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.
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- Citation for previous publication
Pearson JD, Lee JKH, Bacani JTC, Lai R, and Ingham RJ. (2012) NPM-ALK: the prototypic member of a family of oncogenic tyrosine kinases. Journal of Signal Transduction. 2012:123253. (Review Article).Pearson JD, Lee JKH, Bacani JTC, Lai R, and Ingham RJ. (2011) NPM-ALK and the JunB transcription factor regulate the expression of cytotoxic molecules in ALK-positive, anaplastic large cell lymphoma. International Journal of Clinical and Experimental Pathology. 4:124-133.Pearson JD, Mohammed Z, Bacani JTC, Lai R, and Ingham RJ. (2012) The heat shock protein-90 co-chaperone, Cyclophilin 40, promotes ALK-positive anaplastic large cell lymphoma and its regulation is regulated by the NPM-ALK oncoprotein. BMC Cancer. 12:229.
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