Guerrero Carmina Louise Hugo, Yamashita Yoshiko, Miyara Megumi, Imaizumi Naoki, Kato Megumi, Sakihama Shugo, Hayashi Masaki, Miyagi Takashi, Karimata Kaori, Uchihara Junnosuke, Ohshiro Kazuiku, Todoroki Junpei, Nakachi Sawako, Morishima Satoko, Karube Kennosuke, Tanaka Yuetsu, Masuzaki Hiroaki, Fukushima Takuya
Laboratory of Hematoimmunology, Graduate School of Health Sciences, University of the Ryukyus, Nishihara, Japan.
AI Drug Development Division, NEC Corporation, Tokyo, Japan.
Blood Adv. 2020 Mar 24;4(6):1062-1071. doi: 10.1182/bloodadvances.2019001429.
Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type 1 (HTLV-1)-associated T-cell malignancy with generally poor prognosis. Although only ∼5% of HTLV-1 carriers progress to ATL, early diagnosis is challenging because of the lack of ATL biomarkers. In this study, we analyzed blood plasma profiles of asymptomatic HTLV-1 carriers (ACs); untreated ATL patients, including acute, lymphoma, smoldering, and chronic types; and ATL patients in remission. Through SOMAscan, expression levels of 1305 plasma proteins were analyzed in 85 samples (AC, n = 40; ATL, n = 40; remission, n = 5). Using gene set enrichment analysis and gene ontology, overrepresented pathways in ATL vs AC included angiogenesis, inflammation by cytokines and chemokines, interleukin-6 (IL-6)/JAK/STAT3, and notch signaling. In selecting candidate biomarkers, we focused on soluble tumor necrosis factor 2 (sTNFR2) because of its active role in enriched pathways, extreme significance (Welch's t test P < .00001), high discrimination capacity (area under the curve >0.90), and novelty in ATL research. Quantification of sTNFR2 in 102 plasma samples (AC, n = 30; ATL, n = 68; remission, n = 4) using enzyme-linked immunosorbent assay showed remarkable elevations in acute ATL, at least 10 times those of AC samples, and return of sTNFR2 to AC state levels after achieving remission. Flow cytometry and immunostaining validated the expression of TNFR2 in ATL cells. No correlation between sIL-2 and sTNFR2 levels in acute ATL was found, suggesting the possibility of sTNFR2 as an independent biomarker. Our findings represent the first extensive blood-based proteomic analysis of ATL, suggesting the potential clinical utility of sTNFR2 in diagnosing acute ATL.
成人T细胞白血病/淋巴瘤（ATL）是一种与1型人类T细胞白血病病毒（HTLV-1）相关的T细胞恶性肿瘤，预后通常较差。虽然只有约5%的HTLV-1携带者会发展为ATL，但由于缺乏ATL生物标志物，早期诊断具有挑战性。在本研究中，我们分析了无症状HTLV-1携带者（ACs）、未经治疗的ATL患者（包括急性、淋巴瘤、冒烟和慢性类型）以及缓解期ATL患者的血浆谱。通过SOMAscan分析了85个样本（AC，n = 40；ATL，n = 40；缓解期，n = 5）中1305种血浆蛋白的表达水平。使用基因集富集分析和基因本体论，ATL与AC中过度表达的通路包括血管生成、细胞因子和趋化因子介导的炎症、白细胞介素-6（IL-6）/JAK/STAT3和Notch信号通路。在选择候选生物标志物时，我们重点关注可溶性肿瘤坏死因子2（sTNFR2），因为它在富集通路中发挥积极作用、具有极高的显著性（韦尔奇t检验P <.00001）、高辨别能力（曲线下面积>0.90）以及在ATL研究中的新颖性。使用酶联免疫吸附测定法对102个血浆样本（AC，n = 30；ATL，n = 68；缓解期，n = 4）中的sTNFR2进行定量分析，结果显示急性ATL中sTNFR2显著升高，至少是AC样本的10倍，并且在达到缓解后sTNFR2恢复到AC状态水平。流式细胞术和免疫染色验证了TNFR2在ATL细胞中的表达。在急性ATL中未发现sIL-2与sTNFR2水平之间存在相关性，这表明sTNFR2有可能作为一种独立的生物标志物。我们的研究结果代表了对ATL首次进行的基于血液的广泛蛋白质组学分析，表明sTNFR2在诊断急性ATL方面具有潜在的临床应用价值。
