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RNA sequencing identifies clonal structure of T-cell repertoires in patients with adult T-cell leukemia/lymphoma
npj Genomic Medicine ( IF 4.7 ) Pub Date : 2019-05-06 , DOI: 10.1038/s41525-019-0084-9
Amir Farmanbar , Robert Kneller , Sanaz Firouzi

The diversity of T-cell receptor (TCR) repertoires, as generated by somatic DNA rearrangements, is central to immune system function. High-throughput sequencing technologies now allow examination of antigen receptor repertoires at single-nucleotide and, more recently, single-cell resolution. The TCR repertoire can be altered in the context of infections, malignancies or immunological disorders. Here we examined the diversity of TCR clonality and its association with pathogenesis and prognosis in adult T-cell leukemia/lymphoma (ATL), a malignancy caused by infection with human T-cell leukemia virus type-1 (HTLV-1). We analyzed 62 sets of high-throughput RNA sequencing data from 59 samples of HTLV-1−infected individuals—asymptomatic carriers (ACs), smoldering, chronic, acute and lymphoma ATL subtypes—and three uninfected controls to evaluate TCR distribution. Based on these TCR profiles, CD4-positive cells and ACs showed polyclonal patterns, whereas ATL patients showed oligo- or monoclonal patterns (with 446 average clonotypes across samples). Expression of TCRα and TCRβ genes in the dominant clone differed among the samples. ACs, CD4-positive samples and smoldering patients showed significantly higher TCR diversity compared with chronic, acute and lymphoma subtypes. CDR3 sequence length distribution, amino acid conservation and gene usage variability for ATL patients resembled those of peripheral blood cells from ACs and healthy donors. Thus, determining monoclonal architecture and clonal diversity by RNA sequencing might be useful for prognostic purposes and for personalizing ATL diagnosis and assessment of treatments.



中文翻译:

RNA测序可鉴定成人T细胞白血病/淋巴瘤患者T细胞库的克隆结构

体细胞DNA重排产生的T细胞受体(TCR)谱表的多样性对免疫系统功能至关重要。现在,高通量测序技术允许以单核苷酸和最近的单细胞分辨率检查抗原受体库。在感染,恶性肿瘤或免疫性疾病的情况下,TCR的库可能会改变。在这里,我们研究了TCR克隆的多样性及其与成人T细胞白血病/淋巴瘤(ATL)的发病机理和预后的关系,ATL是由人类T细胞白血病病毒1型(HTLV-1)感染引起的恶性肿瘤。我们分析了HTLV-1感染个体的59个样本中的62组高通量RNA测序数据,这些样本包括无症状携带者(ACs),闷烧,慢性,急性和淋巴瘤ATL亚型,以及三个未感染的对照来评估TCR分布。根据这些TCR谱,CD4阳性细胞和AC显示多克隆模式,而ATL患者则显示出寡核苷酸或单克隆模式(样本间平均446种克隆型)。不同样本中优势克隆中TCRα和TCRβ基因的表达不同。AC,CD4-与慢性,急性和淋巴瘤亚型相比,阳性样本和阴燃的患者显示出更高的TCR多样性。ATL患者的CDR3序列长度分布,氨基酸保守性和基因使用变异性类似于AC和健康供体的外周血细胞。因此,通过RNA测序确定单克隆结构和克隆多样性可能对预后和个性化ATL诊断和治疗评估有用。

更新日期:2019-05-06
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