title: NPM-ALK and the JunB transcription factor regulate the expression of cytotoxic molecules in ALK-positive, anaplastic large cell lymphoma.
abstract: Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) is an aggressive non-Hodgkin lymphoma of T/null immunophenotype that is most prevalent in children and young adults. The normal cellular counterpart of this malignancy is presumed to be the cytotoxic T lymphocyte (CTL), and this presumption is partly based on the observation that these tumour cells often express cytotoxic granules containing Granzyme B (GzB) and Perforin. Chromosomal translocations involving the gene encoding for the ALK tyrosine kinase are also characteristic of ALK+ ALCL, and the resulting fusion proteins (e.g. NPM-ALK) initiate signalling events important in ALK+ ALCL pathogenesis. These events include the elevated expression of JunB; an AP-1 family transcription factor that promotes ALK+ ALCL proliferation. In this report we demonstrate that JunB is a direct transcriptional activator of GzB and that GzB transcription is also promoted by NPM-ALK. We found that Perforin expression was not regulated by JunB, but was promoted by NPM-ALK in some cell lines and inhibited by it in others. In conclusion, our study makes the novel observation that signalling through NPM-ALK and JunB affect the expression of cytotoxic molecules in ALK+ ALCL. Moreover, these findings demonstrate the expression of GzB and Perforin in this lymphoma is not solely due its presumed CTL origin, but that oncogenic signalling is actively influencing the expression of these proteins.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Pearson
authors.forename: Jason K H
authors.initials: JK
authors.lastname: Lee
authors.forename: Julinor T C
authors.initials: JT
authors.lastname: Bacani
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ingham
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053804:Granzymes / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D015514:Oncogene Proteins, Fusion; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D054353:Perforin; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D053804:Granzymes