Abstract
Anaplastic large cell lymphoma (ALCL) is characterized by the expression of nucleophosmin‐anaplastic lymphoma kinase (NPM‐ALK). The mechanism of activation of downstream molecules that regulate cell growth in ALCLs has not been elucidated. Using mass spectrometry‐based phosphoproteomic screen, we identified GSK3β as a potential signaling protein of NPM‐ALK. We hypothesize that NPM‐ALK signals through GSK3β and contributes to the oncogenic phenotype of ALCL. To assess the role of GSK3β in NPM‐ALK induced oncogenesis, we utlilized an ALK inhibitor and stable tetracyclin‐inducible shRNA knockdown of NPM‐ALK in ALCL‐derived cell lines. ALCL derived cell lines were evaluated for cell viability and levels of P‐S9GSK3β and NPM‐ALK protein. The expression of P‐S9GSK3β and CDC25A (a known GSK3β substrate) was evaluated in biopsies of ALCL tissues using immunohistochemistry. Inhibition of ALK kinase activity resulted in a dose‐dependent decrease in cell viability which was rescued by a small molecule inhibitor of GSK3β (GSK3 IX). NPM‐ALK kinase activity was critical for the phosphorylation of GSK3β at serine‐9 but not total GSK3β. P‐S9GSK3β and CDC25A were expressed in neoplastic cells of ALCL tissue biopsies. Our results provide support for the role of GSK3β/CDC25A as mediators of NPM‐ALK oncogenesis. Funding support comes from University of Michigan, Department of Pathology development funds.
Published Version
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