The lifelong transcriptomic landscape of human blood cells

Single-cell technologies have transformed our view of normal and malignant hematopoiesis, yet a framework linking lifelong homeostatic hematopoiesis to hematological diseases in blood ecosystem remains incomplete. Here, we constructed a high-resolution landscape of the entire hematopoietic system by integrating transcriptomes of ∼1 million cells from 207 healthy samples spanning five developmental stages (fetal, neonatal, childhood, adult, elderly), and identified 96 blood cell clusters, including a VNN2-marked monocyte subset in the fetus and TSHZ2-marked T cell subsets exhibiting distinct age-dependent dynamics. We uncovered a reversal in hematopoietic stem cell/multipotent progenitor (HSC/MPP) stemness around childhood and a postnatal lymphoid bias shift from reduced early B/T lineage potential to enhanced natural killer (NK) cytotoxicity, coordinately orchestrated by intracellular transcription factor activity and intercellular interactions. Projecting 116 pan-malignancy samples (9 hematological malignancies) to our refined blood cell reference, we identified the upregulation of MYC and MHC II signaling as relatively conserved features correlating with poor prognosis, while hematopoiesis-related modules exhibited subtype-specific distributions with divergent clinical implications. Importantly, we developed a prognostic framework incorporating two core signatures shared across hematological malignancies and subtype-specific features. We further revealed an antagonism between inflammatory and cytotoxic programs across malignancies. Together, we established a panoramic landscape of the human hematopoietic system and elaborated its lifelong behaviors, in which a steady-state reference enabled the delineation of pathological hallmarks across hematological malignancies.