Network model of survival signaling in large granular lymphocyte leukemia

Ranran Zhang, Mithun Vinod Shah, Jun Yang, Susan B. Nyland, Xin Liu, Jong Yun, Reka Z. Albert, Thomas P. Loughran

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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.

Original languageEnglish (US)
Pages (from-to)16308-16313
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number42
DOIs
StatePublished - Oct 21 2008

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Large Granular Lymphocytic Leukemia
Cytotoxic T-Lymphocytes
T-Lymphocytes
Lymphocytes
Survival
Cancer Vaccines
Myeloid Cell Leukemia Sequence 1 Protein
Apoptosis
Interleukin-15
Lymphocyte Activation
Phosphatidylinositol 3-Kinases
Phenotype
Antigens

All Science Journal Classification (ASJC) codes

  • General

Cite this

Zhang, Ranran ; Shah, Mithun Vinod ; Yang, Jun ; Nyland, Susan B. ; Liu, Xin ; Yun, Jong ; Albert, Reka Z. ; Loughran, Thomas P. / Network model of survival signaling in large granular lymphocyte leukemia. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 42. pp. 16308-16313.
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Network model of survival signaling in large granular lymphocyte leukemia. / Zhang, Ranran; Shah, Mithun Vinod; Yang, Jun; Nyland, Susan B.; Liu, Xin; Yun, Jong; Albert, Reka Z.; Loughran, Thomas P.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 42, 21.10.2008, p. 16308-16313.

Research output: Contribution to journalArticle

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AU - Shah, Mithun Vinod

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