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

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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.

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Acknowledgments

This work was supported by grants from the NCI R01CA11211201, the NIH AI056213 and U54RR019397-05. Tipifarnib was provided by the Cancer Therapies Evaluation Program (CTEP). Flow cytometry support was provided by the H. Lee Moffitt Cancer Center Flow Cytometry Core Facility.

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Immunology Program, H. Lee Moffitt Cancer Center, SRB3, 12902 Magnolia Dr, Tampa, FL, 33612, USA

    Fanqi Bai, Alejandro V. Villagra, JianXiang Zou, Jeffrey S. Painter, Kirby Connolly, Julie Y. Djeu, Sheng Wei, Eduardo Sotomayor & Pearlie Epling-Burnette

  2. Drug Discovery Program, H. Lee Moffitt Cancer Center, Tampa, FL, 33612, USA

    Michelle A. Blaskovich & Said Sebti

  3. Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, 17033, USA

    Thomas P. Loughran

  4. Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, 33612, USA

    Lubomir Sokol & Eduardo Sotomayor

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  1. Fanqi Bai
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  2. Alejandro V. Villagra
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Correspondence to Pearlie Epling-Burnette.

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Bai, F., Villagra, A.V., Zou, J. et al. Tipifarnib-mediated suppression of T-bet-dependent signaling pathways. Cancer Immunol Immunother 61, 523–533 (2012). https://doi.org/10.1007/s00262-011-1109-0

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