T memory stem cells are the hierarchical apex of adult T-cell leukemia

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 (T_SCM) 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. T_SCM 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 T_SCM 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. T_SCM 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 T_SCM cells.