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dc.contributor.authorZhang, R
dc.contributor.authorShah, MV
dc.contributor.authorYang, J
dc.contributor.authorNyland, SB
dc.contributor.authoret al
dc.date.accessioned2019-09-04T13:10:31Z
dc.date.available2019-09-04T13:10:31Z
dc.date.issued2008
dc.identifierwww.ncbi.nlm.nih.gov/whalecom0/pubmed/18852469
dc.identifierhttp://hdl.handle.net/11295/30609
dc.identifierhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2571012/
dc.identifier.citationProc Natl Acad Sci U S A. 2008 Oct 21;105(42)en
dc.identifier.urihttps://library.adhl.africa/handle/123456789/7392
dc.description.abstractT cell large granular lymphocyte (T-LGL) leukemia features a clonal expansion of antigen-primed, competent, cytotoxic T lymphocytes (CTL). To systematically understand signaling components that determine the survival of CTL in T-LGL leukemia, we constructed a T-LGL survival signaling network by integrating the signaling pathways involved in normal CTL activation and the known deregulations of survival signaling in leukemic T-LGL. This network was subsequently translated into a predictive, discrete, dynamic model. Our model suggests that the persistence of IL-15 and PDGF is sufficient to reproduce all known deregulations in leukemic T-LGL. This finding leads to the following predictions: (i) Inhibiting PDGF signaling induces apoptosis in leukemic T-LGL. (ii) Sphingosine kinase 1 and NFkappaB are essential for the long-term survival of CTL in T-LGL leukemia. (iii) NFkappaB functions downstream of PI3K and prevents apoptosis through maintaining the expression of myeloid cell leukemia sequence 1. (iv) T box expressed in T cells (T-bet) should be constitutively activated concurrently with NFkappaB activation to reproduce the leukemic T-LGL phenotype. We validated these predictions experimentally. Our study provides a model describing the signaling network involved in maintaining the long-term survival of competent CTL in humans. The model will be useful in identifying potential therapeutic targets for T-LGL leukemia and generating long-term competent CTL necessary for tumor and cancer vaccine development.en
dc.language.isoenen
dc.titleNetwork model of survival signaling in large granular lymphocyte leukemiaen
dc.typeArticleen


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