title: Tipifarnib-mediated suppression of T-bet-dependent signaling pathways.
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.
authors: Immunology Program, H. Lee Moffitt Cancer Center, SRB3, 12902 Magnolia Dr, Tampa, FL 33612, USA.
authors: Fanqi
authors: F
authors: Bai
authors: Alejandro V
authors: AV
authors: Villagra
authors: Jianxiang
authors: J
authors: Zou
authors: Jeffrey S
authors: JS
authors: Painter
authors: Kirby
authors: K
authors: Connolly
authors: Michelle A
authors: MA
authors: Blaskovich
authors: Lubomir
authors: L
authors: Sokol
authors: Said
authors: S
authors: Sebti
authors: Julie Y
authors: JY
authors: Djeu
authors: Thomas P
authors: TP
authors: Loughran
authors: Sheng
authors: S
authors: Wei
authors: Eduardo
authors: E
authors: Sotomayor
authors: Pearlie
authors: P
authors: Epling-Burnette
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy; D054066:Leukemia, Large Granular Lymphocytic / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015363:Quinolones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058408:Th1-Th2 Balance / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D015363:Quinolones; C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins; D051231:Farnesyltranstransferase; C402769:tipifarnib