Kallemeijn Martine J, de Ridder Dick, Schilperoord-Vermeulen Joyce, van der Klift Michèle Y, Sandberg Yorick, van Dongen Jacques J M, Langerak Anton W
Laboratory of Medical Immunology, Department of Immunology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Bioinformatics, Wageningen University, Wageningen, The Netherlands.
PLoS One. 2017 Apr 13;12(4):e0175670. doi: 10.1371/journal.pone.0175670. eCollection 2017.
TCRγδ+ T-LGL leukemia is a rare form of chronic mature T cell disorders in elderly, which is generally characterized by a persistently enlarged CD3+CD57+TCRγδ+ large granular lymphocyte population in the peripheral blood with a monoclonal phenotype. Clinically, the disease is heterogeneous, most patients being largely asymptomatic, although neutropenia, fatigue and B symptoms and underlying diseases such as autoimmune diseases or malignancies are also often observed. The etiology of TCRγδ+ T-LGL proliferations is largely unknown. Here, we aimed to investigate underlying molecular mechanisms of these rare proliferations by performing gene expression profiling of TCRγδ+ T-LGL versus normal TCRγδ+ T cell subsets. From our initial microarray dataset we observed that TCRγδ+ T-LGL leukemia forms a separate group when compared with different healthy control TCRγδ+ T cell subsets, correlating best with the healthy TemRA subset. The lowest correlation was seen with the naive subset. Based on specific comparison between healthy control cells and TCRγδ+ T-LGL leukemia cells we observed up-regulation of survival, proliferation and hematopoietic system related genes, with a remarkable down-regulation of apoptotic pathway genes. RQ-PCR validation of important genes representative for the dataset, including apoptosis (XIAP, CASP1, BCLAF1 and CFLAR), proliferation/development (ID3) and inflammation (CD28, CCR7, CX3CR1 and IFNG) processes largely confirmed the dysregulation in proliferation and apoptosis. Based on these expression data we conclude that TCRγδ+ T-LGL leukemia is likely the result of an underlying aberrant molecular mechanisms leading to increased proliferation and reduced apoptosis.
TCRγδ⁺T淋巴细胞大颗粒淋巴细胞白血病是一种罕见的老年慢性成熟T细胞疾病，其一般特征是外周血中持续存在单克隆表型的CD3⁺CD57⁺TCRγδ⁺大颗粒淋巴细胞群体。临床上，该疾病具有异质性，大多数患者基本无症状，不过也经常观察到中性粒细胞减少、疲劳、B症状以及自身免疫性疾病或恶性肿瘤等基础疾病。TCRγδ⁺T淋巴细胞大颗粒淋巴细胞增殖的病因大多不明。在此，我们旨在通过对TCRγδ⁺T淋巴细胞大颗粒淋巴细胞与正常TCRγδ⁺T细胞亚群进行基因表达谱分析，来研究这些罕见增殖的潜在分子机制。从我们最初的微阵列数据集观察到，与不同的健康对照TCRγδ⁺T细胞亚群相比，TCRγδ⁺T淋巴细胞大颗粒淋巴细胞白血病形成一个单独的组，与健康的终末分化记忆性T细胞亚群相关性最佳。与初始亚群的相关性最低。基于健康对照细胞与TCRγδ⁺T淋巴细胞大颗粒淋巴细胞白血病细胞之间的特异性比较，我们观察到存活、增殖和造血系统相关基因上调，而凋亡途径基因显著下调。对代表该数据集的重要基因进行实时定量聚合酶链反应验证，包括凋亡相关基因（XIAP、CASP1、BCLAF1和CFLAR）、增殖/发育相关基因（ID3）和炎症相关基因（CD28、CCR7、CX3CR1和IFNG），在很大程度上证实了增殖和凋亡的失调。基于这些表达数据，我们得出结论，TCRγδ⁺T淋巴细胞大颗粒淋巴细胞白血病可能是潜在异常分子机制导致增殖增加和凋亡减少的结果。
