Olson Kristine C, Kulling Paige M, Olson Thomas L, Tan Su-Fern, Rainbow Rebecca J, Feith David J, Loughran Thomas P
a University of Virginia Cancer Center , University of Virginia , Charlottesville , VA , USA.
b Department of Medicine, Division of Hematology/Oncology , University of Virginia , Charlottesville , VA , USA.
Cancer Biol Ther. 2017 May 4;18(5):290-303. doi: 10.1080/15384047.2016.1235669. Epub 2016 Oct 7.
Large granular lymphocyte leukemia (LGLL) is a rare incurable chronic disease typically characterized by clonal expansion of CD3+ cytotoxic T-cells. Two signal transducer and activator of transcription factors, STAT1 and STAT3, are constitutively active in T-LGLL. Disruption of this activation induces apoptosis in T-LGLL cells. Therefore, considerable efforts are focused on developing treatments that inhibit STAT activation. Calcitriol, the active form of vitamin D, has been shown to decrease STAT1 and STAT3 phosphorylation in cancer cell lines and autoimmune disease mouse models. Thus, we investigated whether calcitriol could be a valid therapeutic for T-LGLL. Calcitriol treatment of the TL-1 cell line (model of T-LGLL) led to decreased phospho-Y701 STAT1 and phospho-Y705 STAT3 and increased vitamin D receptor (VDR) levels. Doses of 10 and 100 nM calcitriol also significantly decreased the inflammatory cytokine IFN-γ in the TL-1 cell line. The overall cell viability did not change when the TL-1 cell line was treated with 0.1 to 1000 nM calcitriol. Studies with primary T-LGLL patient peripheral blood mononuclear cells showed that the majority of T-LGLL patients have detectable VDR and activated STATs in contrast to normal donor controls. Treatment of primary T-LGLL patient cells with calcitriol recapitulated findings from the TL-1 cell line. Overall, our results suggest that calcitriol may reprogram T-cells to decrease essential STAT activation and pro-inflammatory cytokine output. These data support further investigation into calcitriol as an experimental therapeutic for T-LGLL.
大颗粒淋巴细胞白血病（LGLL）是一种罕见的不可治愈的慢性疾病，其典型特征是CD3+细胞毒性T细胞的克隆性扩增。两种信号转导和转录激活因子，即信号转导与转录激活因子1（STAT1）和信号转导与转录激活因子3（STAT3），在T细胞大颗粒淋巴细胞白血病（T-LGLL）中持续激活。这种激活的破坏会诱导T-LGLL细胞凋亡。因此，大量的努力都集中在开发抑制STAT激活的治疗方法上。骨化三醇，即维生素D的活性形式，已被证明可降低癌细胞系和自身免疫性疾病小鼠模型中STAT1和STAT3的磷酸化水平。因此，我们研究了骨化三醇是否可能是T-LGLL的有效治疗方法。用骨化三醇处理TL-1细胞系（T-LGLL模型）导致磷酸化Y701 STAT1和磷酸化Y705 STAT3水平降低，维生素D受体（VDR）水平升高。10和100 nM剂量的骨化三醇也显著降低了TL-1细胞系中的炎性细胞因子干扰素-γ（IFN-γ）。当用0.1至1000 nM骨化三醇处理TL-1细胞系时，总体细胞活力没有变化。对原发性T-LGLL患者外周血单个核细胞的研究表明，与正常供体对照相比，大多数T-LGLL患者可检测到VDR和激活的STATs。用骨化三醇处理原发性T-LGLL患者细胞重现了TL-1细胞系的研究结果。总体而言，我们的结果表明，骨化三醇可能对T细胞进行重编程，以降低必需的STAT激活和促炎细胞因子的产生。这些数据支持进一步研究将骨化三醇作为T-LGLL的实验性治疗方法。
