Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1182/blood.2019001289

Type

Journal

Blood

Publication Date

05/08/2019

Addresses

Paediatrics, University of Oxford, United Kingdom.