Firouzi Sanaz, Farmanbar Amir, Nakai Kenta, Iwanaga Masako, Uchimaru Kaoru, Utsunomiya Atae, Suzuki Yutaka, Watanabe Toshiki
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, and.
Laboratory of Functional Analysis in Silico, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Blood Adv. 2017 Jun 27;1(15):1195-1205. doi: 10.1182/bloodadvances.2017005900.
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops along a carcinogenic process involving 5 or more genetic events in infected cells. The lifetime incidence of ATL among HTLV-1-infected individuals is approximately 5%. Although epidemiologic studies have revealed risk factors for ATL, the molecular mechanisms that determine the fates of carriers remain unclear. A better understanding of clonal composition and related longitudinal dynamics would clarify the process of ATL leukemogenesis and provide insights into the mechanisms underlying the proliferation of a malignant clone. Genomic DNA samples and clinical information were obtained from individuals enrolled in the Joint Study for Predisposing Factors for ATL Development, a Japanese prospective cohort study. Forty-seven longitudinal samples from 20 individuals (9 asymptomatic carriers and 11 patients with ATL at enrollment) were subjected to a clonality analysis. A method based on next-generation sequencing was used to characterize clones on the basis of integration sites. Relationships were analyzed among clonal patterns, clone sizes, and clinical status, including ATL onset and progression. Among carriers, those exhibiting an oligoclonal or monoclonal pattern with largely expanded clones subsequently progressed to ATL. All indolent patients who progressed to acute-type ATL exhibited monoclonal expansion. In both situations, the major expanded clone after progression was derived from the largest pre-existing clone. This study has provided the first detailed information regarding the dynamics of HTLV-1-infected T-cell clones and collectively suggests that the clonality of HTLV-1-infected cells could be a useful predictive marker of ATL onset and progression.
成人T细胞白血病（ATL）是一种侵袭性T细胞恶性肿瘤，由1型人类T细胞白血病病毒（HTLV-1）引起，其致癌过程涉及受感染细胞中的5个或更多基因事件。HTLV-1感染个体中ATL的终生发病率约为5%。尽管流行病学研究揭示了ATL的危险因素，但决定携带者命运的分子机制仍不清楚。更好地了解克隆组成和相关的纵向动态将阐明ATL白血病发生的过程，并为恶性克隆增殖的潜在机制提供见解。基因组DNA样本和临床信息来自参与ATL发病易感因素联合研究的个体，这是一项日本前瞻性队列研究。对来自20名个体（9名无症状携带者和11名入组时患有ATL的患者）的47个纵向样本进行了克隆性分析。一种基于下一代测序的方法被用于根据整合位点来表征克隆。分析了克隆模式、克隆大小和临床状态之间的关系，包括ATL的发病和进展。在携带者中，那些表现出寡克隆或单克隆模式且克隆大量扩增的个体随后进展为ATL。所有进展为急性型ATL的惰性患者均表现出单克隆扩增。在这两种情况下，进展后主要扩增的克隆均源自最大的预先存在的克隆。这项研究提供了关于HTLV-1感染T细胞克隆动态的首个详细信息，并总体表明HTLV-1感染细胞的克隆性可能是ATL发病和进展的有用预测标志物。
