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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3374-3383.
Prepublished online as a Blood First Edition Paper on August 9, 2007; DOI 10.1182/blood-2007-02-071258.
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Submitted February 1, 2007
Accepted August 5, 2007
The oncoprotein NPM-ALK of anaplastic large cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling
Philipp B Staber*, Paul Vesely, Naznin Haq, Rene G Ott, Kotaro Funato, Isabella Bambach, Claudia Fuchs, Silvia Schauer, Werner Linkesch, Andelko Hrzenjak, Wilhelm G Dirks, Veronika Sexl, Helmut Bergler, Marshall E. Kadin, David W. Sternberg, Lukas Kenner, and Gerald Hoefler
Klinische Abteilung fur Hamatologie, Universitatsklinik fur Innere Medizin, Medizinische Universitat, Graz, Austria
Institut fur Pathologie, Medizinische Universitat, Graz, Austria
Mount Sinai School of Medicine, New York, NY, United States
Institut fur Pharmakologie, Universitat Wien, Wien, Austria
Deutsche Sammlung von Mikroorganismen und Zellkulturen, GmbH (DSMZ), Braunschweig, Germany
Institut fur Molekulare Biowissenschaften, Karl-Franzens Universitat, Graz, Austria
Roger Williams Medical Center, Providence, RI, & Dept of Dermatology, Brigham & Women's Hospital, Boston, MA, United States
Institut fur Pathologie, Medizinsche Universitat Wien, and Boltzmann Institute for Cancer Research, Vienna, Austria
* Corresponding author; email: philipp.staber{at}meduni-graz.at.
Anaplastic large cell lymphomas (ALCL) are highly proliferating tumors that commonly express the AP-1 transcription factor JunB. ALK fusions occur in about 50% of ALCL, and among these 80% have the t(2;5) translocation with NPM-ALK expression. We report greater activity of JunB in NPM-ALK positive than in NPM-ALK negative ALCL. Specific knockdown of JUNB mRNA using small interfering RNA and small hairpin RNA in NPM-ALK expressing cells decreases cellular proliferation as evidenced by a reduced cell count in the G2/M phase of the cell cycle. Expression of NPM-ALK results in ERK1/2 activation and transcriptional upregulation of JUNB. Both NPM-ALK positive and negative ALCL tumors demonstrate active ERK1/2 signaling. In contrast to NPM-ALK negative ALCL, the mTOR pathway is active in NPM-ALK positive lymphomas. Pharmacological inhibition of mTOR in NPM-ALK positive cells downregulates JunB protein levels by shifting JUNB mRNA translation from large polysomes to monosomes and ribonucleic particles (RNPs), and decreases cellular proliferation. Thus, JunB is a critical target of mTOR and is translationally regulated in NPM-ALK positive lymphomas. This is the first study demonstrating translational control of AP-1 transcription factors in human neoplasia. In conjunction with NPM-ALK, JunB enhances cell cycle progression and may therefore represent a therapeutic target.
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