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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1668-1676. Prepublished online as a Blood First Edition Paper on April 27, 2006; DOI 10.1182/blood-2006-04-015586. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-015586v1 108/5/1668    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 Rudelius, M. Articles by Raffeld, M. Search for Related Content PubMed PubMed Citation Articles by Rudelius, M. Articles by Raffeld, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 11, 2006 Accepted April 16, 2006 Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma Martina Rudelius, Stefania Pittaluga, Satoshi Nishizuka, Trinh H-T Pham, Falko Fend, Elaine S Jaffe, Leticia Quintanilla-Martinez, and Mark Raffeld* Hematopathology Section, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD Molecular Therapeutics Program, National Cancer Institute, NIH, Bethesda, MD Institute of Pathology Technical University of Munich, Munich, Germany GSF-National Research Center for Health and Environment, Neuherberg, Germany * Corresponding author; email: mraff{at}box-m.nih.gov. To determine whether the PI3K/Akt signaling pathway is involved in the pathogenesis of mantle cell lymphoma (MCL), we investigated the phosphorylation status of Akt and multiple downstream targets in primary MCL cases and cell lines. Akt was phosphorylated in 12/12 aggressive blastoid MCL variants and in 4/4 MCL cell lines. In contrast, phosphorylated Akt was present in only 5/16 typical MCL, 3 at comparable levels to the blastoid cases, and 2 at low levels. The presence of p-Akt was accompanied by the phosphorylation of p27kip1, FRKHL-1, MDM2, Bad, mTOR, and p70S6K. Inhibition of the PI3K/Akt pathway in the MCL cell lines abrogated or reduced the phosphorylation of Akt, p27kip1, FRKHL-1, MDM2, Bad, mTOR, GSK-3, IB, and led to cell cycle arrest and apoptosis. Six MCL cases (5 with activated Akt and one with inactive Akt), and 3/4 cell lines showed loss of PTEN expression. PI3KCA mutations were not detected. We conclude that constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis of MCL, and preferentially occurs in blastoid variants. One possible mechanism of activation is loss of PTEN expression. These data suggest that PI3K/Akt inhibitors may be effective in the treatment of Akt-activated MCL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: AKTion on mantle cell lymphoma Michael R. Gold Blood 2006 108: 1425-1426. [Full Text] [PDF] This article has been cited by other articles: A. Psyrri, S. Papageorgiou, E. Liakata, A. Scorilas, D. Rontogianni, C. K. Kontos, P. Argyriou, D. Pectasides, N. Harhalakis, V. Pappa, et al. Phosphatidylinositol 3'-Kinase Catalytic Subunit {alpha} Gene Amplification Contributes to the Pathogenesis of Mantle Cell Lymphoma Clin. Cancer Res., September 15, 2009; 15(18): 5724 - 5732. [Abstract] [Full Text] [PDF] D. S. Levy, J. A. Kahana, and R. Kumar AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines Blood, February 19, 2009; 113(8): 1723 - 1729. [Abstract] [Full Text] [PDF] Y. Tabe, D. Sebasigari, L. Jin, M. Rudelius, T. Davies-Hill, K. Miyake, T. Miida, S. Pittaluga, and M. Raffeld MDM2 Antagonist Nutlin-3 Displays Antiproliferative and Proapoptotic Activity in Mantle Cell Lymphoma Clin. Cancer Res., February 1, 2009; 15(3): 933 - 942. [Abstract] [Full Text] [PDF] P. Gelebart, M. Anand, H. Armanious, A. C. Peters, J. Dien Bard, H. M. Amin, and R. Lai Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma Blood, December 15, 2008; 112(13): 5171 - 5179. [Abstract] [Full Text] [PDF] B. Sun, X. Zhang, S. Talathi, and B. S. Cummings Inhibition of Ca2+-Independent Phospholipase A2 Decreases Prostate Cancer Cell Growth by p53-Dependent and Independent Mechanisms J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 59 - 68. [Abstract] [Full Text] [PDF] J. Dal Col, P. Zancai, L. Terrin, M. Guidoboni, M. Ponzoni, A. Pavan, M. Spina, S. Bergamin, S. Rizzo, U. Tirelli, et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma Blood, May 15, 2008; 111(10): 5142 - 5151. [Abstract] [Full Text] [PDF]

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