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Role of the oncoprotein FOXM1 in NPM-ALK+ anaplastic large cell lymphoma

  • Author / Creator
    Haque, Moinul
  • Forkhead Box M1 (FOXM1) is a transcription factor which belongs to the evolutionary conserved Forkhead protein family. FOXM1 has been implicated in the pathogenesis of several solid and hematologic cancers. In this study, the significance of FOXM1 in NPM-ALK-positive anaplastic large cell lymphoma (NPM-ALK+ ALCL)—a childhood cancer—was assessed, with a focus on how FOXM1 interacts with NPM-ALK, a key oncogenic driver in these tumors. FOXM1 was highly expressed in NPM-ALK+ ALCL cell lines, patient samples and tumors arising in NPM-ALK transgenic mice. FOXM1 was found localized in the nuclei and confirmed to be transcriptionally active in NPM-ALK+ ALCL cells. Inhibition of FOXM1 in NPM-ALK+ ALCL cells using shRNA or a pharmacologic agent (thiostrepton) resulted in significant reductions in cell growth and soft-agar colony formation, which were associated with apoptosis and cell-cycle arrest. FOXM1 is functionally linked to NPM-ALK, as FOXM1 enhanced the phosphorylation of the NPM-ALK/STAT3 axis. NPM-ALK was found to influence the transcriptional activity of FOXM1. Specifically, FOXM1 failed to effectively bind to DNA when NPM-ALK was siRNA-silenced or when kinase-dead NPM-ALK variant was tested. Moreover, FOXM1 was found to coimmunoprecipitate with NPM-ALK, which was previously shown to exist as NPM-ALK:NPM1 heterodimers in the nuclei. Further studies showed that this binding of FOXM1 to NPM-ALK hinges on the meditator nucleophosmin (NPM1) and the phosphorylation status of NPM-ALK. In conclusion, this study identified FOXM1 as an important oncogenic protein in NPM-ALK+ ALCL. This study exemplified that NPM-ALK can exert oncogenic effects in the nuclei by regulating FOXM1 and illustrated an additional role of NPM1 in the context of NPM-ALK pathobiology.

  • Subjects / Keywords
  • Graduation date
    Fall 2019
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-tzge-gx64
  • License
    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.