Cancer Immunology, Immunotherapy

, Volume 61, Issue 4, pp 523–533

Tipifarnib-mediated suppression of T-bet-dependent signaling pathways

  • Fanqi Bai
  • Alejandro V. Villagra
  • JianXiang Zou
  • Jeffrey S. Painter
  • Kirby Connolly
  • Michelle A. Blaskovich
  • Lubomir Sokol
  • Said Sebti
  • Julie Y. Djeu
  • Thomas P. Loughran
  • Sheng Wei
  • Eduardo Sotomayor
  • Pearlie Epling-Burnette
Original article

DOI: 10.1007/s00262-011-1109-0

Cite this article as:
Bai, F., Villagra, A.V., Zou, J. et al. Cancer Immunol Immunother (2012) 61: 523. doi:10.1007/s00262-011-1109-0

Abstract

Large granular lymphocyte (LGL) leukemia is a chronic lymphoproliferative disease in which T-bet [T-box transcription factor 21 gene (tbx21)] overexpression may play a pathogenic role. T-bet orchestrates the differentiation of mature peripheral T-cells into interferon-γ (IFN-γ) and tumor necrosis factor-α producing CD4+ T-helper type I (Th1) and CD8+ T cytotoxic cells that are necessary for antiviral responses. When IL-12 is produced by antigen–presenting cells, T-bet expression is induced, causing direct stimulation of ifng gene transcription while simultaneously acting as a transcriptional repressor of the IL4 gene, which then leads to Th1 dominance and T-helper type 2 differentiation blockade. Additionally, T-bet has been shown to regulate histone acetylation of the ifng promoter and enhancer to loosen condensed DNA, creating greater accessibility for other transcription factor binding, which further amplifies IFNγ production. We found that treatment with a farnesyltransferase inhibitor tipifarnib reduced Th1 cytokines in LGL leukemia patient T-cells and blocked T-bet protein expression and IL-12 responsiveness in T-cells from healthy donors. The mechanism of suppression was based on modulation of histone acetylation of the ifng gene, which culminated in Th1 blockade.

Keywords

Farnesyltransferase inhibitors Immunomodulatory T-bet Large granular lymphocyte leukemia Interferon Histone acetylation 

Supplementary material

262_2011_1109_MOESM1_ESM.pdf (95 kb)
Supplementary material 1 (PDF 95 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Fanqi Bai
    • 1
  • Alejandro V. Villagra
    • 1
  • JianXiang Zou
    • 1
  • Jeffrey S. Painter
    • 1
  • Kirby Connolly
    • 1
  • Michelle A. Blaskovich
    • 2
  • Lubomir Sokol
    • 4
  • Said Sebti
    • 2
  • Julie Y. Djeu
    • 1
  • Thomas P. Loughran
    • 3
  • Sheng Wei
    • 1
  • Eduardo Sotomayor
    • 1
    • 4
  • Pearlie Epling-Burnette
    • 1
  1. 1.Immunology Program, H. Lee Moffitt Cancer CenterTampaUSA
  2. 2.Drug Discovery Program, H. Lee Moffitt Cancer CenterTampaUSA
  3. 3.Penn State Cancer Institute, Penn State College of MedicineHersheyUSA
  4. 4.Department of Malignant HematologyH. Lee Moffitt Cancer CenterTampaUSA
  5. 5.James A. Haley VA HospitalTampaUSA