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Human lymphopoiesis is a dynamic life-long process that starts in utero 6 weeks post-conception. Fetal B-lymphopoiesis remains poorly defined and yet is key to understanding leukemia initiation in early life. Here, we provide a comprehensive analysis of the human fetal B-cell developmental hierarchy. We report the presence in fetal tissues of two distinct CD19+ B-progenitors, an adult-type CD10+ve ProB-progenitor and a new CD10-ve PreProB-progenitor, and describe their molecular and functional characteristics. PreProB- and ProB-progenitors appear early in the first trimester in embryonic liver, followed by a sustained second wave of B-progenitor development in fetal BM, where together they form >40% of the total HSC/progenitor pool. Almost one-third of fetal B-progenitors are CD10-ve PreProB-progenitors while, by contrast, PreProB-progenitors are almost undetectable (0.53{plus minus}0.24%) in adult BM. Single-cell transcriptomics and functional assays place fetal PreProB- upstream of ProB-progenitors, identifying them as the first B-lymphoid restricted progenitor in human fetal life. Fetal BM PreProB- and ProB-progenitors both give rise solely to B-lineage cells yet they are transcriptionally distinct. Like their fetal counterparts, adult BM PreProB-progenitors give rise only to B-lineage cells in vitro and express the expected B-lineage gene expression program. However, fetal PreProB-progenitors, display a distinct, ontogeny-related gene expression pattern which is not seen in adult PreProB-progenitors; and share transcriptomic signatures with CD10-ve B-progenitor infant acute lymphoblastic leukemia blast cells. These data identify PreProB-progenitors as the earliest B-lymphoid-restricted progenitor in human fetal life, and suggest that this fetal-restricted committed B-progenitor might provide a permissive cellular context for prenatal B-progenitor leukemia initiation.

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Paediatrics, University of Oxford, United Kingdom.