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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4655-4664. Prepublished online as a Blood First Edition Paper on August 6, 2008; DOI 10.1182/blood-2008-02-139105. This Article Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2008-02-139105v1 112/12/4655    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 Zebedin, E. Articles by Sexl, V. Search for Related Content PubMed PubMed Citation Articles by Zebedin, E. Articles by Sexl, V. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 12, 2008 Accepted July 9, 2008 Leukemic challenge unmasks a requirement for PI3K in NK-cell-mediated tumor surveillance Eva Zebedin, Olivia Simma, Christian Schuster, Eva Maria Putz, Sabine Fajmann, Wolfgang Warsch, Eva Eckelhart, Dagmar Stoiber, Eva Weisz, Johannes A Schmid, Winfried F Pickl, Christian Baumgartner, Peter Valent, Roland P Piekorz, Michael Freissmuth, and Veronika Sexl* Institute of Pharmacology, Medical University of Vienna, Vienna, Austria Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria Institute of Immunology, Medical University of Vienna, Vienna, Austria Institute of Internal Medicine I, Medical University of Vienna, Vienna, Austria Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University, Duesseldorf, Germany * Corresponding author; email: veronika.sexl{at}meduniwien.ac.at. Specific inhibitors of PI3K-isoforms are currently evaluated for their therapeutic potential in leukemia. We found that bcr/abl-positive human leukemic cells express PI3K and therefore explored its impact on leukemia development. Using PI3K-deficient mice we define a dual role of PI3K in leukemia. We observed a growth-promoting effect in tumor cells and an essential function in NK-cell-mediated tumor surveillance: Abelson-transformed PI3K-deficient cells induced leukemia in RAG2-deficient mice with an increased latency indicating that PI3K accelerated leukemia progression in vivo. However, the absence of PI3K also affected NK-cell-mediated tumor surveillance. PI3K-deficient NK-cells failed to lyse a large variety of target cells because of defective degranulation as also documented by capacitance recordings. Accordingly, transplanted leukemic cells killed PI3K-deficient animals more rapidly. As a net effect, no difference in disease latency in vivo was detected if both - leukemic cells and NK-cells - lack PI3K. Other tumor models confirmed that PI3K-deficient mice succumbed more rapidly when challenged with T- or B-lymphoid leukemic or B16 melanoma cells. Thus, the action of PI3K in the NK-compartment is as relevant to survival of the mice as the delayed tumor progression. This dual function must be taken into account when employing PI3K-inhibitors as anti-leukemic agents in clinical trials. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The dilemma of anticancer therapy: tumor-specific versus immune effects Laurence Zitvogel and Guido Kroemer Blood 2008 112: 4364-4365. [Full Text] [PDF] This article has been cited by other articles: A. Saudemont, F. Garcon, H. Yadi, M. Roche-Molina, N. Kim, A. Segonds-Pichon, A. Martin-Fontecha, K. Okkenhaug, and F. Colucci p110{gamma} and p110{delta} isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease PNAS, April 7, 2009; 106(14): 5795 - 5800. [Abstract] [Full Text] [PDF]

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