The lifelong transcriptomic landscape of human blood cells

Single-cell technologies have transformed our understanding of normal and malignant hematopoiesis, yet a framework linking lifelong homeostatic hematopoiesis with hematological diseases remains incomplete. In this study, we constructed a high-resolution atlas of human hematopoiesis across the lifespan by integrating transcriptomic profiles of nearly one million cells from healthy individuals spanning five developmental stages. This comprehensive atlas revealed previously unrecognized blood cell populations, including a fetal VNN2-marked monocyte subset and age-associated TSHZ2-marked T cell subsets. Leveraging this atlas, we uncovered a reversal of hematopoietic stem cell/multipotent progenitor (HSC/MPP) stemness during childhood and revealed a postnatal remodeling of lymphoid potential, characterized by reduced early B/T lineage potential and enhanced natural killer cell cytotoxicity. These lifelong hematopoietic dynamics were coordinately regulated by intracellular transcription factors and intercellular interactions. Furthermore, this atlas enabled systematic interpretation of the features of hematological malignancies. Mapping malignant samples onto the healthy reference revealed conserved disease-associated programs, including MYC and MHC II signaling activation, as well as subtype-specific hematopoietic signatures with distinct clinical implications. We further established a prognostic framework integrating shared and disease-specific signatures across malignancies. Together, this study establishes a comprehensive reference framework for deciphering human blood development, aging, and disease.