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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4622-4629. Prepublished online as a Blood First Edition Paper on February 12, 2004; DOI 10.1182/blood-2003-03-0820. This Article Full Text (PDF) All Versions of this Article: 2003-03-0820v1 103/12/4622    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gu, T.-L. Articles by Sternberg, D. W Search for Related Content PubMed PubMed Citation Articles by Gu, T.-L. Articles by Sternberg, D. W Social Bookmarking                   What's this? Submitted March 18, 2003 Accepted January 12, 2004 The NPM-ALK Fusion Kinase of Anaplastic Large Cell Lymphoma Regulates Survival and Proliferative Signaling Through Modulation of FOXO3a Ting-Lei Gu, Zuzana Tothova, Blanca Scheijen, James D Griffin, D G Gilliland, and David W Sternberg* Harvard Medical School, Boston, MA, USA Hematology Division, Brigham and Women's Hospital, Boston, MA, USA Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA; Hematology Division, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Howard Hughes Medical Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA; Hematology Division, Brigham and Women's Hospital, Boston, MA, USA * Corresponding author; email: dsternberg{at}partners.org. 30-50% of patients with advanced stage anaplastic large cell lymphoma (ALCL) harbor the balanced chromosomal rearrangement t(2;5)(p23;q35), which results in the generation of the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). In order to further study survival signaling by NPM-ALK, we generated Ba/F3 cell lines with either inducible or constitutive expression of NPM-ALK and examined the regulation of the AKT target FOXO3a. We hypothesized that NPM-ALK signaling through PI 3-kinase and AKT would regulate FOXO3a, a member of the forkhead family of transcription factors, and thereby stimulate proliferation and block programmed cell death in NPM-ALK-transformed cells. In Ba/F3 cells with induced or constitutive expression of NPM-ALK, concomitant AKT activation and phosphorylation of its substrate FOXO3a was observed. In addition, transient expression of NPM-ALK in U-20S cells inhibited FOXO3a-mediated transactivation of reporter-gene expression. Furthermore, NPM-ALK-induced FOXO3a phosphorylation in Ba/F3 cells resulted in nuclear exclusion of this transcriptional regulator, upregulation of Cyclin D2 expression, and downregulation of p27kip1 and Bim-1 expression. NPM-ALK reversal of proliferation arrest and of p27kip1 induction was dependent on phosphorylation of FOXO3a. Thus, FOXO3a is a barrier to hematopoietic transformation that is overcome by phosphorylation and cytoplasmic relocalization induced by expression of NPM-ALK. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z. Jagani, K. Song, J. L. Kutok, M. R. Dewar, A. Melet, T. Santos, A. Grassian, S. Ghaffari, C. Wu, R. Ren, et al. Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL-Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors Cancer Res., August 15, 2009; 69(16): 6546 - 6555. [Abstract] [Full Text] [PDF] P. Shi, R. Lai, Q. Lin, A. S. Iqbal, L. C. Young, L. W. Kwak, R. J. Ford, and H. M. 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