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, Gerald Hoefler

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

Anaplastic large cell lymphomas (ALCLs) are highly proliferating tumors that commonly express the AP-1 transcription factor JunB. ALK fusions occur in approximately 50% of ALCLs, 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 ALCLs. 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 up-regulation of JUNB. Both NPM-ALK -positive and -negativeALCL 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 down-regulates 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.

Original languageEnglish
Pages (from-to)3374-3383
Number of pages10
JournalBlood
Volume110
Issue number9
DOIs
StatePublished - 1 Nov 2007

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