Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511, Japan.
Department of Oncology, Karmanos Cancer Institute, Detroit, MI 48201.
Proc Natl Acad Sci U S A. 2020 May 26;117(21):11685-11691. doi: 10.1073/pnas.1920346117. Epub 2020 May 11.
Human T cell leukemia virus 1 (HTLV-1) causes the functionally debilitating disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as adult T cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-y prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-y, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1-infected cells. Genomic analysis revealed that somatic mutations of HTLV-1-infected cells were seen in 90% of these cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1-infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.
人类 T 细胞白血病病毒 1（HTLV-1）可引起功能障碍性疾病 HTLV-1 相关性脊髓病/热带痉挛性截瘫（HAM/TSP）以及成人 T 细胞白血病淋巴瘤（ATLL）。尽管人们担心 ATLL 的发展可能会影响 HAM/TSP 的死亡率，但在这一领域缺乏前瞻性证据。在这项为期 5 年的前瞻性队列研究中，我们确定了 527 例 HAM/TSP 患者的 ATLL 死亡率、患病率和发病率。HAM/TSP 患者的标准死亡率比为 2.25，ATLL 是死亡的主要原因之一（33 例死亡中的 5 例）。这些患者的 ATLL 患病率和发病率分别为 3.0%和 3.81/1000 人年。为了确定发生 ATLL 的高风险患者，我们对 218 例 HAM/TSP 患者的另一队列进行了流式细胞术、Southern 印迹和靶向测序数据分析。在 17%的 HAM/TSP 患者中，我们发现细胞黏附分子 1（CADM1）阳性的 T 细胞增加，CADM1 是 ATLL 和 HTLV-1 感染细胞的标志物。基因组分析显示，90%的病例中可见 HTLV-1 感染细胞的体细胞突变，其中 11%的病例出现优势克隆，并在纵向观察中发展为 ATLL。在这项研究中，我们能够证明 HAM/TSP 患者的死亡率增加，以及 ATLL 对其预后的显著影响。具有 ATLL 相关体细胞突变的 HTLV-1 感染细胞的优势克隆扩增可能是 HAM/TSP 患者中具有更高风险发展为 ATLL 的重要特征。
