T 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 NFκB are essential for the long-term survival of CTL in T-LGL leukemia. (iii) NFκB 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 NFκB 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.
%0 Journal Article
%1 Zhang2008Network
%A Zhang, Ranran
%A Shah, Mithun V.
%A Yang, Jun
%A Nyland, Susan B.
%A Liu, Xin
%A Yun, Jong K.
%A Albert, Réka
%A Loughran, Thomas P.
%D 2008
%I National Academy of Sciences
%J Proceedings of the National Academy of Sciences
%K cancer, leukemia, signalling-network biological-networks
%N 42
%P 16308--16313
%R 10.1073/pnas.0806447105
%T Network model of survival signaling in large granular lymphocyte leukemia
%U http://dx.doi.org/10.1073/pnas.0806447105
%V 105
%X T 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 NFκB are essential for the long-term survival of CTL in T-LGL leukemia. (iii) NFκB 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 NFκB 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.
@article{Zhang2008Network,
abstract = {{T 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 NFκB are essential for the long-term survival of CTL in T-LGL leukemia. (iii) NFκB 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 NFκB 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.}},
added-at = {2019-06-10T14:53:09.000+0200},
author = {Zhang, Ranran and Shah, Mithun V. and Yang, Jun and Nyland, Susan B. and Liu, Xin and Yun, Jong K. and Albert, R\'{e}ka and Loughran, Thomas P.},
biburl = {https://www.bibsonomy.org/bibtex/219fb6b4761691a254209d03de681f13f/nonancourt},
citeulike-article-id = {3575904},
citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0806447105},
citeulike-linkout-1 = {http://www.pnas.org/content/105/42/16308.abstract},
citeulike-linkout-2 = {http://www.pnas.org/content/105/42/16308.full.pdf},
citeulike-linkout-3 = {http://www.pnas.org/cgi/content/abstract/105/42/16308},
citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/18852469},
citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=18852469},
day = 21,
doi = {10.1073/pnas.0806447105},
interhash = {19a10b9541e7ed363ecafcf48f71df4a},
intrahash = {19fb6b4761691a254209d03de681f13f},
issn = {1091-6490},
journal = {Proceedings of the National Academy of Sciences},
keywords = {cancer, leukemia, signalling-network biological-networks},
month = oct,
number = 42,
pages = {16308--16313},
pmid = {18852469},
posted-at = {2014-06-05 17:27:07},
priority = {2},
publisher = {National Academy of Sciences},
timestamp = {2019-07-31T13:50:37.000+0200},
title = {{Network model of survival signaling in large granular lymphocyte leukemia}},
url = {http://dx.doi.org/10.1073/pnas.0806447105},
volume = 105,
year = 2008
}