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Blood, 1 August 2008, Vol. 112, No. 3, pp. 770-781. Prepublished online as a Blood First Edition Paper on May 13, 2008; DOI 10.1182/blood-2007-11-121871. This Article Full Text (PDF) Supplemental Methods and Tables All Versions of this Article: blood-2007-11-121871v1 112/3/770    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 Shah, M. V. Articles by Loughran, T. P. Search for Related Content PubMed PubMed Citation Articles by Shah, M. V. Articles by Loughran, T. P., Jr. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 6, 2007 Accepted April 1, 2008 Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes Mithun Vinod Shah, Ranran Zhang, Rosalyn Irby, Ravi Kothapalli, Xin Liu, Ty Arrington, Bryan Frank, Norman H. Lee, and Thomas P. Loughran Jr.* Penn State Cancer Institute, Penn State, Hershey, PA, United States Shriners Hospital for Children, Shriners Hospital for Children, Tampa, FL, United States Pharmacology & Physiology, George Washington University Medical Center, Washington, DC, United States * Corresponding author; email: tloughran{at}psu.edu. T-cell large granular lymphocyte (LGL) leukemia is characterized by clonal expansion of CD3+ CD8+ cells. Leukemic LGL correspond to terminally differentiated effector-memory cytotoxic T-lymphocytes (CTL) that escape Fas-mediated activation-induced cell death (AICD) in vivo. The gene expression signature of peripheral blood mononuclear cells from thirty LGL leukemia patients showed profound dysregulation of expression of apoptotic genes and suggested uncoupling of activation and apoptotic pathways as a mechanism for failure of AICD in leukemic LGL. Pathway based microarray analysis indicated that balance of pro-apoptotic and anti-apoptotic sphingolipid mediated signaling was deregulated in leukemic LGL. We further investigated sphingolipid pathways and found that acid ceramidase was constitutively overexpressed in leukemic LGL and that its inhibition induced apoptosis of leukemic LGL. We also showed that S1P5 is the predominant S1P-receptor in leukemic LGL, while S1P1 is downregulated. FTY720, a functional antagonist of S1P-mediated signaling, induced apoptosis in leukemic LGL and also sensitized leukemic LGL to Fas-mediated death. Collectively, these results show a role for sphingolipid-mediated signaling as a mechanism for long-term survival of CTL. Therapeutic targeting of this pathway, such as use of FTY720, may have efficacy in LGL leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Zambello and G. Semenzato Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches Haematologica, October 1, 2009; 94(10): 1341 - 1345. [Full Text] [PDF] S. J. Richards A "pathogenetic" role for CMV in CD4+ LGL proliferations Blood, December 1, 2008; 112(12): 4367 - 4368. [Full Text] [PDF] R. Zhang, M. V. Shah, J. Yang, S. B. Nyland, X. Liu, J. K. Yun, R. Albert, and T. P. Loughran Jr. Network model of survival signaling in large granular lymphocyte leukemia PNAS, October 21, 2008; 105(42): 16308 - 16313. [Abstract] [Full Text] [PDF]

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