Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Blood. 2015 Jun 4;125(23):3527-35. doi: 10.1182/blood-2014-10-607465. Epub 2015 Apr 6.
Adult T-cell leukemia (ATL) is a peripheral CD4(+) T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). Despite several investigations using human specimens and mice models, the exact origin of ATL cells remains unclear. Here we provide a new insight into the hierarchical architecture of ATL cells. HTLV-1-infected cells and dominant ATL clones are successfully traced back to CD45RA(+) T memory stem (TSCM) cells, which were recently identified as a unique population with stemlike properties, despite the fact that the majority of ATL cells are CD45RA(-)CD45RO(+) conventional memory T cells. TSCM cells from ATL patients are capable of both sustaining themselves in less proliferative mode and differentiating into other memory T-cell populations in the rapidly propagating phase. In a xenograft model, a low number of TSCM cells efficiently repopulate identical ATL clones and replenish downstream CD45RO(+) memory T cells, whereas other populations have no such capacities. Taken together, these findings demonstrate the phenotypic and functional heterogeneity and the hierarchy of ATL cells. TSCM cells are identified as the hierarchical apex capable of reconstituting identical ATL clones. Thus, this is the first report to demonstrate the association of a T-cell malignancy with TSCM cells.
成人 T 细胞白血病（ATL）是一种由人类 T 细胞白血病病毒 1 型（HTLV-1）引起的外周 CD4(+)T 细胞肿瘤。尽管使用人类标本和小鼠模型进行了多次研究，但 ATL 细胞的确切起源仍不清楚。在这里，我们提供了对 ATL 细胞层次结构的新见解。成功地追踪到 HTLV-1 感染细胞和主导 ATL 克隆来源于 CD45RA(+)T 记忆干细胞（TSCM）细胞，尽管大多数 ATL 细胞是 CD45RA(-)CD45RO(+)常规记忆 T 细胞，但最近发现 TSCM 细胞是具有干细胞特性的独特群体。来自 ATL 患者的 TSCM 细胞既能以较低的增殖模式维持自身，又能在快速增殖阶段分化为其他记忆 T 细胞群体。在异种移植模型中，少量的 TSCM 细胞能够有效地重新填充相同的 ATL 克隆并补充下游 CD45RO(+)记忆 T 细胞，而其他群体则没有这种能力。总之，这些发现表明了 ATL 细胞的表型和功能异质性和层次结构。TSCM 细胞被确定为能够重建相同 ATL 克隆的层次顶端。因此，这是首次报道证明 T 细胞恶性肿瘤与 TSCM 细胞有关。
