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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4834-4840. Prepublished online as a Blood First Edition Paper on February 16, 2006; DOI 10.1182/blood-2005-08-3076. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-08-3076v1 107/12/4834    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Schade, A. E. Articles by Maciejewski, J. P. Search for Related Content PubMed PubMed Citation Articles by Schade, A. E. Articles by Maciejewski, J. P. Related Collections Immunobiology Neoplasia Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Phosphatidylinositol-3-phosphate kinase pathway activation protects leukemic large granular lymphocytes from undergoing homeostatic apoptosis Andrew E. Schade, Jennifer J. Powers, Marcin W. Wlodarski, and Jaroslaw P. Maciejewski From the Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic Foundation, OH; the Department of Clinical Pathology, Cleveland Clinic, OH; and Institute of Medical Immunology, Charité Medical School, Berlin, Germany. T-cell large granular lymphocytic leukemia (T-LGL) is characterized by chronic clonal lymphoproliferation of cytotoxic T lymphocytes (CTLs). Despite exhibiting phenotypic properties of antigen-activated cells, including expression of Fas and FasL, T-LGL cells accumulate and demonstrate resistance to apoptosis. We propose that increased activity of a prosurvival signaling pathway in T-LGL is responsible for attenuated apoptosis in T-LGL. Given the importance of the phosphatidylinositol-3 kinase (PI3K)–AKT pathway in regulating the balance between survival and apoptosis, we analyzed AKT activity in T-LGL cells. Compared with resting CTLs from healthy donors, patients' T-LGL cells showed higher levels of phosphorylated AKT. We demonstrate that phospho-AKT induction is dependent on the upstream activity of a Src family kinase. Since the PI3K-AKT pathway can antagonize the ability of Fas to initiate apoptosis, we hypothesized that inhibition of PI3K would lead to reacquisition of Fas sensitivity in T-LGL. Inhibition of the PI3K-AKT pathway alone led to brisk spontaneous apoptosis of T-LGL. These results suggest that T-LGL pathogenesis is dependent on activity of the PI3K-AKT pathway, without which the leukemic cells will begin to undergo spontaneous apoptosis. We propose that novel therapeutics inhibiting the PI3K-AKT axis may provide effective treatment for T-LGL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. W. Wlodarski, Z. Nearman, A. Jankowska, N. Babel, J. Powers, P. Leahy, H.-D. Volk, and J. P. Maciejewski Phenotypic differences between healthy effector CTL and leukemic LGL cells support the notion of antigen-triggered clonal transformation in T-LGL leukemia J. Leukoc. Biol., March 1, 2008; 83(3): 589 - 601. [Abstract] [Full Text] [PDF] A. E. Schade, G. L. Schieven, R. Townsend, A. M. Jankowska, V. Susulic, R. Zhang, H. Szpurka, and J. P. Maciejewski Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation Blood, February 1, 2008; 111(3): 1366 - 1377. [Abstract] [Full Text] [PDF] J. Thomas, J. K. Haseman, J. I. Goodman, J. M. Ward, T. P. Loughran Jr, and P. J. Spencer A Review of Large Granular Lymphocytic Leukemia in Fischer 344 Rats as an Initial Step Toward Evaluating the Implication of the Endpoint to Human Cancer Risk Assessment Toxicol. Sci., September 1, 2007; 99(1): 3 - 19. [Abstract] [Full Text] [PDF] M. Y. Follo, S. Mongiorgi, C. Bosi, A. Cappellini, C. Finelli, F. Chiarini, V. Papa, M. Libra, G. Martinelli, L. Cocco, et al. The Akt/Mammalian Target of Rapamycin Signal Transduction Pathway Is Activated in High-Risk Myelodysplastic Syndromes and Influences Cell Survival and Proliferation Cancer Res., May 1, 2007; 67(9): 4287 - 4294. [Abstract] [Full Text] [PDF]

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